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Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival

Qi Wang, Joshua L Johnson, Nathalie Y.R Agar and 1 more

PLoS Biology · 2008

doi:10.1371/journal.pbio.0060170

Abstract

The nature of the "toxic gain of function" that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with roughly 10% of the cases being inherited or familial. The cause of sporadic ALS (sALS) is unknown while familial ALS (fALS) is known to be caused by mutations in six different genes and six different chromosomal loci. One of these genes encoding Cu/Zn-superoxide dismutase (SOD1) was found to associate with 20% of fALS, and at least 119 fALS-associated SOD1 mutations have been characterized in humans.

Fifteen years after the discovery that SOD1 mutations can cause ALS, the mechanisms of toxicity are still not well understood. The dominant inheritance of most SOD1 mutations and the literature as a whole indicate that SOD1 mutations result in a toxic gain of function rather than a loss of function. Numerous hypotheses have been proposed, reviewed in, and can be broken down conceptually into the (nonexclusive) toxic mechanisms that converge to SOD1 protein structure–function and those that converge elsewhere (downstream effects). Popular hypotheses for SOD1 variant structure and function changes include decreased stability of apo or metallated SOD1, increased hydrophobicity and aggregation propensity, susceptibility to posttranslational modification, loss of metals, and aberrant chemistry. Popular hypotheses for downstream effects include impairment of axonal transport, impairment of proteasome or chaperone activity, and mitochondrial or endoplasmic reticulum–Golgi dysfunction. Notably, the only potentially toxic property thus far shared by all fALS SOD1 variants is an increased propensity to form proteinaceous aggregates. Due to the clinical similarities between fALS and sALS, research into SOD1 mutation-related fALS may provide insight into sporadic cases. Here we demonstrate that two properties, namely, increased aggregation propensity and instability (loss of stability), are major contributors to SOD1 toxicity in ALS patients. On the basis of these results we rationalize the determinants of aggregation, the selective vulnerability of neurons, and patient survival times.

SOD1 Mutations Have Inherently Different Toxicities

The goal of this study is to discover the mechanisms of toxicity of fALS SOD1 mutations. Neurologists often publish the age at onset and the time from disease onset to death (also termed survival or disease duration) for their ALS patients, thereby enabling epidemiological studies that assess the risk of a given variable, which for this study include given mutations' relative toxicity and physical characteristics (physicochemical parameters). Previous studies revealed that different SOD1 mutations have inherently different toxicities (encode different mean disease durations). We expanded upon these studies with a larger set of fALS-causing SOD1 mutations as well as larger patient cohorts. Hazard ratios (relative risk of dying at a given time) of fALS SOD1 mutations and non-SOD1-related fALS compared to that of sALS were obtained from the Cox proportional hazard model (Table 1). From this result, fALS SOD1 mutations with data from at least five individual patients (full criteria for inclusion are defined in the Materials and Methods section) were significantly related to different hazards. Kaplan–Meier survival curves from patients with fALS-causing SOD1 mutations, non-SOD1-related fALS, and sALS were generated. Figure 1 illustrates that fALS SOD1 mutations encode different prognoses, ranging from considerably better (e.g., H46R, hazard rate = 0.075 × sALS) to considerably worse (e.g., A4V, hazard rate = 5.7 × sALS) than sALS. Moreover, the Log rank, Breslow, and Tarone–Ware tests, which also compare patient survival rates (i.e., each mutation versus every other fALS-causing SOD1 mutation, non-SOD1-related fALS, and sALS) using different mathematical functions, confirm that different SOD1 mutations have inherently different prognoses (Table 2).

SOD1 Variants' Gain of Hydrophobicity, Loss of α-Helix, and Gain of β-Sheet Propensity Are fALS Risk Factors, While Loss of Net Charge Is Protective

To test the hypothesis that changes to the physicochemical properties of SOD1 variants are toxic, specifically those properties known to influence protein aggregation, physicochemical properties for each protein variant (hydrophobicity, propensity to lose α-helices, form β-sheets, protein net charge, etc.) were evaluated in a Cox proportional hazard model (Table 3). The hazard ratios were significantly higher than 1.0 for mutations that either increase hydrophobicity, lose α-helices, or form β-sheets. In contrast, mutations that decrease the magnitude of the protein net charge correlate with hazard ratios significantly smaller than 1.0. These results indicate that changes in the SOD1 variants' properties, specifically increases in hydrophobicity and propensity to lose α-helices and to form β-sheets, correlate with decreased fALS patient survival, while decreases of the magnitude of net charge correlate with increased fALS patient survival, in contradiction with previous reports.

Dobson and co-workers introduced an equation (termed the Chiti–Dobson equation herein) to predict the changes of aggregation rates of unfolded peptides or proteins upon point mutations by their physicochemical properties. This equation was derived empirically by modeling how three physicochemical properties, hydrophobicity, secondary structure (including loss of α-helix and gain of β-sheet), and protein net charge, change upon mutations (the hazard analyses for each of these properties were reported in the previous paragraph). These physicochemical property changes then were related to changes in protein aggregation rate, yielding an equation that predicts how any mutation will change the rate of protein aggregation (the predicted change of aggregation rate is referred to as the aggregation propensity). Although this equation is empirical, it is based upon first physical/chemical principles and approximates how a given mutation will change the energy (and thus the equilibrium) between a solvated and an aggregated protein. The Chiti–Dobson equation is ln(νmut/νwt) = 0.633ΔHydr + 0.198(ΔΔG coil-α + ΔΔG β-coil) – 0.491Δcharge, in which ln(νmut/νwt) represents change of aggregation rate upon mutation, and ΔHydr, ΔΔG coil-α, ΔΔG β-coil, and Δcharge represent the changes of hydrophobicity, free energy change for the process from α-helix to random coil, free energy change for the process from random coil to β-sheet, and protein net charge from the mutation, respectively. In their landmark study, it was demonstrated that increases in hydrophobicity, losses of α-helices, gains of β-sheets, and decreases in the magnitude of protein net charge increase the rate of protein aggregation.

Protein Aggregation Propensity Is a Risk Factor of fALS

The Chiti–Dobson equation and the many equations it inspired are robust and versatile, having successfully predicted aggregation rates of diverse disease-associated proteins, including amyloid β-peptide, tau, α-synuclein, amylin, lysozyme, etc. Moreover, increases in the predicted rates of aggregation of various mutations in amyloid β-peptide were shown to relate to increased neuronal dysfunction and degeneration in a Drosophila model of Alzheimer's disease. To test the hypothesis that protein aggregation propensity is related to fALS patient survival, the Chiti–Dobson equation was used to predict the aggregation propensities of fALS-causing SOD1 mutations. We started this study by validating the Chiti–Dobson equation, taking all experimental protein aggregation rate data available at the inception of our study (data reported as of 2005, listed in Table 4) and recalibrating the equation. The detailed results of the validation are reported in Figure 2. In summary, the Chiti–Dobson equation was verified for use in fALS, and the statistical correlation between the physicochemical parameters (hydrophobicity, net charge, and secondary structure) and the aggregation propensity remained and changed only marginally. Since the time we validated the Chiti–Dobson equation, a number of papers also validated their general approach. Even so, we have included our own analysis since it provides exposure to the physical basis of aggregation propensity. Furthermore, inclusion of this data makes this study self-contained so that all of the data necessary to support or disprove our model are contained herein. Notably, this paper's conclusions were the same using both the original and the recalibrated Chiti–Dobson equation.

The average patient survival times for different SOD1 variants with measured thermodynamic stabilities were plotted against corresponding predicted aggregation propensities, and linear regression analysis weighted by the number of patients for each mutation yielded R (multiple correlation coefficient, with a larger value indicating a stronger relationship) and P (value less than 0.05 implies a significant result) values of 0.58 and <0.001, respectively (Figure 3A). The severity of fALS thus is related to mutation-induced increases in SOD1 aggregation propensity. The same plot was performed with the linear regression analysis not weighted by the number of patients (Figure 4A), yielding R and P values of 0.23 and 0.2, respectively. Unfortunately, the published epidemiology data do not provide the information necessary to stratify for known ALS covariates, including lifestyle (diet and smoking), palliative care, bulbar onset, etc., and weighted data are more likely to account for differences in these factors. The Chiti–Dobson equation results for all fALS-causing SOD1 mutations with patients' survival data also were evaluated in a univariate Cox proportional hazard model (Table 3). The hazard ratio for the Chiti–Dobson equation result was significantly higher than 1.0, which also indicates that aggregation propensity is a risk factor for fALS. Previous studies of Huntington's disease revealed an inverse relationship between the length of glutamine repeat of huntingtin and age of disease onset. The authors of this previous study concluded that disease onset correlates with rate of nucleation of aggregation. We demonstrate here an inverse relationship between the rate of aggregation elongation after nucleation and the disease duration after onset.

Protein Instability Is a Risk Factor for fALS

On the basis of our observation that predicted increased protein aggregation correlates with increased disease severity and previous data indicating that protein unfolding or misfolding promote aggregation, we tested the hypothesis that a loss of protein stability also could be a risk factor for ALS. For the sake of simplicity, we use the term instability throughout this article, with instability defined as the inverse of either the normalized ΔΔG (unfolding free energy change difference between mutant and wild-type SOD1) or normalized ΔT m (melting point difference between mutant and wild-type SOD1). Instability was considered for two reasons: (1) the Chiti–Dobson equation predicts the aggregation rates of unfolded proteins (it was derived from the aggregation rates of proteins in high trifluoroethanol concentrations that contained secondary but no tertiary structure), and therefore, formally, unfolding must occur prior to aggregation, and (2) unfolding is known to speed protein aggregation in vitro to the extent that without chemically induced unfolding induction periods extend from months to years, as demonstrated for SOD1. Aggregation in vivo therefore may require protein unfolding. Before using stability data published by different laboratories using different methods (melting point, which yields ΔT m, or chaotroph-induced unfolding, which yields ΔΔG), we sought to determine the reliability of the data. If different laboratories reported similar values of stability for the same mutants, then the data could be deemed reliable. Therefore, all published measurements of apo SOD1 stability (metallated SOD1 calorimetry data often bear the characteristics of irreversible denaturation, probably via Cu-catalyzed disulfide bond formation, and is therefore less reliable) were compiled, and the experimental values of ΔΔG and ΔT m were normalized to the range from 0 to 1 (described in the Materials and Methods section), with 0 representing the least stable, and 1 representing the most stable (highest stability) variant. Through the use of all of the data from mutants where ΔΔG and ΔT m were measured by different laboratories, a plot of normalized ΔΔG versus normalized ΔT m was created. Good interlaboratory correlation of measured stability values was observed (slope = 0.94, R = 0.90, P = 0.002; Figure 5), and we therefore deemed the stability data reliable for use.

Next, patient survival data for fALS-causing SOD1 variants were plotted against corresponding instability values, and linear regression analysis weighted by the number of patients for each mutation yielded R and P values of 0.71 and <0.001, respectively (Figure 3B). The same plot was performed with the linear regression analysis not weighted by the number of patients (Figure 4B), yielding R = 0.34 and P = 0.07. A gain of SOD1 instability (loss of stability) upon mutation therefore is related to decreased fALS patient survival. Increased in vitro instability is consistent with previous findings that the in vivo half-lives of SOD1 variants are decreased.

Protein Aggregation Propensity and Protein Instability Are Synergistic Risk Factors for fALS

Previous results from computer simulations indicate a multistep process for aggregation via destabilization, encouraging us to understand the combined effect of aggregation propensity and protein instability upon ALS patient survival. On the basis of their respective multiple correlation coefficients and slopes, aggregation propensity and instability are equal contributors to fALS patients' survival. Moreover, no obvious correlation between protein instability and aggregation propensity was observed for the SOD1 variants used in Figure 3 (Figure S1), indicating that increased instability is not responsible for the increased predicted protein aggregation propensity. The combination of instability and aggregation propensity represents the relative energy in proceeding from folded to unfolded apo SOD1 and then from unfolded to aggregated states. Patient survival was plotted against corresponding summed instability and aggregation propensity values. A linear regression analysis weighted by the number of patients for each mutation yielded R and P values of 0.83 and <0.001, respectively (Figure 3C). The same plot was performed with the linear regression analysis not weighted by the number of patients (Figure 4C), yielding R = 0.47 and P = 0.01. The improved statistical result of predicting patient survival after combining instability and aggregation propensity indicates that aggregation occurs from unfolded or partially unfolded SOD1. The stability data used herein were for apo SOD1, and therefore the absence of metals is implicit. The R 2 value was 0.69 from the weighted data, indicating that 69% of the intrinsic variability these fALS patients' survival resulted from the combination of increased aggregation propensity and instability. Additionally, aggregation propensity and instability were evaluated in a Cox proportional hazard model (Table 5). The hazard ratios were significantly higher than 1.0 for both factors. The sum of aggregation propensity and instability also was evaluated in a univariate Cox proportional hazard model (Table 5). The hazard ratio for this sum was also significantly higher than 1.0, further indicating that aggregation propensity and instability are synergistic risk factors for fALS. Note that the aggregation propensity and instability tested in Table 5 were normalized to the range from 0 to 1 (as in Figures 3 and 4), while the values tested in Table 3 were not normalized. As a result of normalization, which decreased the value range of tested factors, the hazard ratios of Table 5 are much larger than Table 3, and therefore the large values of hazard ratios reported in Table 5 should not be overinterpreted. Significantly, a fALS patient with an SOD1 mutation of relatively low aggregation propensity and high stability is expected to survive longer after disease onset. It has not escaped our attention that the rate of protein aggregation has implications in both sporadic diseases and aging; for example, the toxicity of a given posttranslational modification is a function of its effect on protein stability and aggregation propensity.

Discussion

We describe here synergistic gains of toxic functions of SOD1 in ALS. These are the first results in any neurodegenerative disease demonstrating that protein instability and aggregation propensity are synergistic risk factors. The fact that there are two synergistic risk factors rather than a single toxic gain of function probably has delayed the discovery of the mechanisms of fALS mutant SOD1 toxicity. The SOD1 stability data used in this paper were measured from apo SOD1, and the aggregation rate data used to create the Chiti–Dobson model were from in vitro unfolded proteins. Therefore, formally, the combination of instability and aggregation propensity represents the relative energy in proceeding from apo folded to unfolded SOD1 and then from unfolded to aggregated states. It has been demonstrated experimentally that apo SOD1 has a faster rate of aggregation than that of holo forms. Partial unfolding/misfolding also can lead to aggregation, and our results cannot rule out a role for the aggregation of partially folded, including metallated, SOD1. Previous studies revealed a correlation and conversely a lack of correlation between SOD1 variant stability and patient disease duration. Correlation between SOD1 variant stability and patient disease duration, however, required that the authors omit stability data of 4 of the 15 variants from their regression analysis (on the basis that these variants change the net charge of SOD1).

As presented in Table 3, SOD1 variants' loss of net charge correlates with increased patient survival, while gain of hydrophobicity, loss of α-helix, and gain of β-sheet propensity are ALS risk factors. On the basis of Dobson and co-workers' related work, a loss of net charge is predicted to increase the aggregation propensity of unfolded proteins. If aggregation is toxic, then one would expect loss of net charge to be toxic. In contrast to the synergistic effects for aggregation propensity and instability presented in Table 5, the correlation of loss of net charge with increased survival has an effect of decreasing the hazard ratio presented in the univariate model presented in Table 3. We demonstrate that mutations causing the entire protein to approach neutrality are protective in the context of fALS (Table 3) rather than deleterious as proposed by Oliveberg and co-workers. These results should be cautiously interpreted since in contrast to our Cox proportional hazard model result that loss of net charge is protective, the mean patient survival for loss of net charge and gain of net charge mutations, unweighted by the number of patients, are 7.1 and 6.9 years, respectively. Further study clearly is required to understand the role of charge in ALS etiology.

In contrast with the strong familiality shown for disease duration after onset (Table 1), SOD1-mediated ALS showed modest familiality with respect to onset, accounting for only 42% of the variability in A4V and D90A fALS patients, and with only G37R and L38V mutations of SOD1 being significant covariates of age of onset. The same analysis shown in Figures 3 and 4 was performed using age at disease onset rather than disease duration as the dependant variable (Figure S2), and little or no relationship between disease onset and aggregation propensity or instability was observed. The Chiti–Dobson equation predicts the rate of aggregation after nucleation (rate of elongation). It is tempting therefore to speculate that the rate of nucleation is a determinant of age at onset. Testing this hypothesis would require the development of a model that can predict nucleation rates based upon physicochemical parameters, a task that is hampered by the stochastic nature of in vitro nucleation times but that should now be possible given our recent development of methods for modeling in vitro nucleation kinetics.

Although our model accounts for 69% of the variability in fALS patient survival after onset, there are clearly genetic components of fALS that our model cannot account for. For example, while D90A is normally a dominantly inherited mutation in North America, 2.5% of people in Sweden and Finland are heterozygous asymptomatic carriers of the D90A SOD1 mutation and require two mutant alleles before presenting ALS symptoms. Notably, our results and conclusions were unaffected by including or excluding D90A survival times during data analysis.

It is postulated that diseases for which protein aggregation contributes to patient death will (1) develop in cells with the highest concentration of the aggregation-prone protein in accordance with the concentration dependence of aggregation rates and (2) have a prognosis influenced by the aggregation propensity of the aggregating protein, in accordance with the results reported herein. Motor neurons are the cells in the ventral horn of the spinal cord with the highest SOD1 concentration, perhaps explaining an aspect of the selective vulnerability of these cells.

Protein aggregation is a hallmark of many neurodegenerative diseases, including ALS. The toxicity of aggregation is fiercely debated (reviewed in), fueled by reproducible evidence that aggregates can be toxic, have no effect, or be protective. We propose that aggregates on either extreme of size, i.e., small protofibrillar aggregates or aggregates large enough to clog axons, are more toxic, while midsize microscopically visible aggregates are less toxic. Our data indicate that the increased aggregation propensity of SOD1 is related to decreased survival of ALS patients. Notably aggregation of SOD1 has been demonstrated in fALS and a subset of sALS patients, 18 fALS rodent models of 13 different SOD1 mutations, and at least 13 SOD1 mutants in cell models.

Familial ALS patients' disease duration and age of onset.

Familial ALS patients' data were taken from all of the available literature. Disease duration was initiated with onset of the first symptoms until the patient's death or when respiratory assistance was required for patients' survival. The average duration and onset for each mutation were calculated as the weighted average based on the number of patients (Table 6). If the patients were still reported to be alive without respiratory assistance at the end of a study, then their disease durations were not used to calculate the average unless the known duration value was larger than the average calculated with only durations from patients deceased or with respiratory assistance. For studies reporting average disease duration and Kaplan–Meier curves, the reported average durations were used to calculate the weighted averages. The current unavailability of http://www.alsod.org/ made it impossible to review the references provided by the website (from which we had taken survival times before it became unavailable), which created the risk of counting a patient's disease onset or survival twice, and made reproducing our study impossible for other groups. We therefore opted not to report data from this website in this study, thereby eliminating no more than 67 (there were 67 http://www.alsod.org/ patients' data without accompanying literature references that may, or may not, have been represented by our literature search) of 1319 patients' data. However, we did perform a complete, alternative set of analyses that did include http://www.alsod.org/ data (unpublished data), and the statistical correlations in the figures and tables shown herein persisted. Mean values of disease durations also were obtained from Kaplan–Meier curves and tested on SOD1 mutations with known experimental thermodynamic stabilities, and the results were comparable to those in Figure 3. Since the weighted average method can provide disease duration regardless of the number of patients, we opted for its use.

Kaplan–Meier survival curves, the log rank tests, and the Cox proportional hazard model.

Kaplan–Meier curves of survival for different fALS-causing SOD1 mutations, non-SOD1-related fALS, and sALS were generated. The hazard ratios of different fALS-causing SOD1 mutations and non-SOD1-related fALS compared to sALS were tested as a category variable by Cox proportional hazard model analysis. For studies reporting Kaplan–Meier curves but without individual patients' data, the Engauge Digitizer 4.1 software was used to obtain coordinates for cumulative survival at each time point. This information was used to calculate the number of patients not surviving at each time point under the assumption that there is no censored patient (with unknown exact survival time because of being alive at the end of study, lost to follow-up, or withdrawal from the study) within the course of survival curves. For cumulative survival not reaching 0 at the end of study, those fractions of patients were treated as censored. The error of the estimated number of patients is less than 5% of the number reported. To eliminate the chance that one or two patients' survival data bias the analysis result, a rule of thumb requiring that each tested fALS-related SOD1 mutation includes at least five noncensored patients was applied. Since patients' survival was reported only as an average from a group of patients and individual patient's survival information was not described in some publications, one or two publications' survival data might bias the analysis result. To eliminate this chance of bias, the rule of thumb was modified as requiring at least five independent descriptions of noncensored patients' survival data (a reported average without individual patient's survival information was treated as one description). The statistical analysis was performed with the software SPSS 15.0 (SPSS, Inc.).

Aggregation propensity calculated from the Chiti–Dobson equation.

The hydrophobicity, β-sheet propensity, and charge values for the amino acid residues were obtained from the Supplementary Information of. While applying the AGADIR algorithm at http://www.embl-heidelberg.de/Services/serrano/agadir/agadir-start.html to obtain α-helical propensities for wild-type (wt) and mutant (mut) P α wt and P α mut values for ΔΔG coil-α calculation for human SOD1, the parameters of pH 7, 310 K, and ionic strength of 0.100 were used. For the protein human SOD1, the N terminus is acetylated, and the C terminus is free in vivo. After the prediction at the residue level was output, the value in the column “Hel” at a specific residue was taken as P α. If a value of 0 for P α was obtained, then 0.1 was added to both P α wt and P α mut values for the correct mathematical meaning of ln(P α wt/P α mut) (F. Chiti, personal communication). The Chiti–Dobson equation terms, Δhydrophobicity, Δcharge, ΔΔG coil-α, and ΔΔG β-coil, were calculated based on equations illustrated in the legend of Table 1 of. The ln(νmut/νwt) values were calculated based on Equation 1 from and normalized from 0 to 1 using the equation normalized aggregation propensity = (aggregation propensity before normalization – MINap)/(MAXap – MINap), with MINap and MAXap as the minimum and maximum aggregation propensities of fALS-causing mutations with known thermodynamic stabilities, respectively, so that the larger normalized values correlate to larger aggregation propensities.

Normalized ΔΔG.

The free energy change difference (ΔΔG) and melting temperature difference (ΔT m) of unfolding a pathogenic variant and wild-type protein are parameters used to characterize the thermodynamic stability of a protein. ΔΔG values were taken from Table 2 of. To graph with other protein stability data, the ΔΔG values were normalized by applying the equation normalized ΔΔG = (ΔΔG values before normalization – MINΔΔG)/(MAXΔΔG – MINΔΔG), with MINΔΔG and MAXΔΔG as the minimum and maximum values of ΔΔG in this dataset, respectively.

Normalized ΔT m.

ΔT m values were taken from Table 1 of, Table 1 of, Table 2 of, Table 3 of, and Table II of. ΔT m values from were averaged for each mutation. Those results then were averaged with the ΔT m values from to determine the ΔT m values for given mutations. The normalized ΔT m values were obtained by applying the equation normalized ΔT m = (average ΔT m values before normalization – MINΔTm)/(MAXΔTm – MINΔTm), with MINΔTm and MAXΔTm as the minimum and maximum values of averaged ΔT m values in this dataset, respectively.

Thermodynamic instability of SOD1 variants.

The instability values for SOD1 variants were obtained from the equation normalized instability = 1 – average of normalized ΔΔG and normalized ΔT m for each mutation, so instability values are simply (1 – normalized ΔΔG or ΔT m), and larger values correlate to less stable variants.

The normalized aggregation propensity and instability for each variant were summed and normalized to the range from 0 to 1 to consider the two factors together.

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    Furukawa Y, Fu R, Deng HX, Siddique T, O'Halloran TV. Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proc Natl Acad Sci U S A. 2006;103:7148-7153.

    Not in our library10.1073/pnas.0602048103

  25. 25.

    Agar J, Durham H. Relevance of oxidative injury in the pathogenesis of motor neuron diseases. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:232-242.

    Not in our library10.1080/14660820310011278

  26. 26.

    Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS. Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem. 1997;69:1936-1944.

    Not in our library10.1046/j.1471-4159.1997.69051936.x

  27. 27.

    Roberts BR, Tainer JA, Getzoff ED, Malencik DA, Anderson SR, et al. Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS. J Mol Biol. 2007;373:877-890.

    Not in our library10.1016/j.jmb.2007.07.043

  28. 28.

    Elam JS, Taylor AB, Strange R, Antonyuk S, Doucette PA, et al. Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS. Nat Struct Biol. 2003;10:461-467.

    Not in our library10.1038/nsb935

  29. 29.

    Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, et al. The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. J Mol Biol. 2003;328:877-891.

    Not in our library10.1016/s0022-2836(03)00355-3

  30. 30.

    Arnesano F, Banci L, Bertini I, Martinelli M, Furukawa Y, et al. The unusually stable quaternary structure of human Cu,Zn-superoxide dismutase 1 is controlled by both metal occupancy and disulfide status. J Biol Chem. 2004;279:47998-48003.

    Not in our library10.1074/jbc.m406021200

  31. 31.

    Furukawa Y, O'Halloran TV. Amyotrophic lateral sclerosis mutations have the greatest destabilizing effect on the apo- and reduced form of SOD1, leading to unfolding and oxidative aggregation. J Biol Chem. 2005;280:17266-17274.

    Not in our library10.1074/jbc.m500482200

  32. 32.

    Banci L, Bertini I, Durazo A, Girotto S, Gralla EB, et al. Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: a possible general mechanism for familial ALS. Proc Natl Acad Sci U S A. 2007;104:11263-11267.

    Not in our library10.1073/pnas.0704307104

  33. 33.

    Bruijn LI, Beal MF, Becher MW, Schulz JB, Wong PC, et al. Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc Natl Acad Sci U S A. 1997;94:7606-7611.

    Not in our library10.1073/pnas.94.14.7606

  34. 34.

    Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature. 1993;364:584.

    Not in our library10.1038/364584a0

  35. 35.

    Crow JP, Ye YZ, Strong M, Kirk M, Barnes S, et al. Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L. J Neurochem. 1997;69:1945-1953.

    Not in our library10.1046/j.1471-4159.1997.69051945.x

  36. 36.

    Wiedau-Pazos M, Goto JJ, Rabizadeh S, Gralla EB, Roe JA, et al. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science. 1996;271:515-518.

    Not in our library10.1126/science.271.5248.515

  37. 37.

    Yim HS, Kang JH, Chock PB, Stadtman ER, Yim MB. A familial amyotrophic lateral sclerosis-associated A4V Cu, Zn-superoxide dismutase mutant has a lower Km for hydrogen peroxide. Correlation between clinical severity and the Km value. J Biol Chem. 1997;272:8861-8863.

    Not in our library10.1074/jbc.272.14.8861

  38. 38.

    Durham HD, Kabashi E, Taylor DM, Agar JN, Stefanis L, Keller JN. The proteasome in neurodegeneration. Motor Neuron Disease. 2007;247-264.

    Not in our library

  39. 39.

    Kabashi E, Agar JN, Taylor DM, Minotti S, Durham HD. Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004;89:1325-1335.

    Not in our library10.1111/j.1471-4159.2004.02453.x

  40. 40.

    Kabashi E, Durham HD. Failure of protein quality control in amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762:1038-1050.

    Not in our library10.1016/j.bbadis.2006.06.006

  41. 41.

    Leigh PN, Dodson A, Swash M, Brion JP, Anderton BH. Cytoskeletal abnormalities in motor neuron disease. An immunocytochemical study. Brain. 1989;112:521-535.

    Not in our library10.1093/brain/112.2.521

  42. 42.

    Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003;300:808-812.

    Not in our library10.1126/science.1083129

  43. 43.

    Collard JF, Cote F, Julien JP. Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature. 1995;375:61-64.

    Not in our library10.1038/375061a0

  44. 44.

    Allen S, Heath PR, Kirby J, Wharton SB, Cookson MR, et al. Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. J Biol Chem. 2003;278:6371-6383.

    Not in our library10.1074/jbc.m209915200

  45. 45.

    Urushitani M, Kurisu J, Tsukita K, Takahashi R. Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J Neurochem. 2002;83:1030-1042.

    Not in our library10.1046/j.1471-4159.2002.01211.x

  46. 46.

    Bruening W, Roy J, Giasson B, Figlewicz DA, Mushynski WE, et al. Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. J Neurochem. 1999;72:693-699.

    Not in our library10.1046/j.1471-4159.1999.0720693.x

  47. 47.

    Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, et al. Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. J Biol Chem. 2005;280:17725-17731.

    Not in our library10.1074/jbc.m501705200

  48. 48.

    Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999;46:787-790.

    Not in our library10.1002/1531-8249(199911)46:5<787::aid-ana17>3.0.co;2-8

  49. 49.
    Human Cu/Zn Superoxide Dismutase (SOD1) Overexpression in Mice Causes Mitochondrial Vacuolization, Axonal Degeneration, and Premature Motoneuron Death and Accelerates Motoneuron Disease in Mice Expressing a Familial Amyotrophic Lateral Sclerosis Mutant SOD1 · 2000
    Not checked
  50. 50.

    Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, et al. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 2001;102:293-305.

    Not in our library10.1007/s004010100399

  51. 51.

    Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998;18:3241-3250.

    Not in our library10.1523/jneurosci.18-09-03241.1998

  52. 52.

    Liu J, Lillo C, Jonsson PA, Vande Velde C, Ward CM, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004;43:5-17.

    Not in our library10.1016/j.neuron.2004.06.016

  53. 53.

    Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain. 2000;123:1339-1348.

    Not in our library10.1093/brain/123.7.1339

  54. 54.

    Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol. 1994;145:1271-1279.

    Not in our library

  55. 55.

    Mourelatos Z, Gonatas NK, Stieber A, Gurney ME, Dal Canto MC. The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc Natl Acad Sci U S A. 1996;93:5472-5477.

    Not in our library10.1073/pnas.93.11.5472

  56. 56.

    Wang J, Xu G, Borchelt DR. High molecular weight complexes of mutant superoxide dismutase 1: age-dependent and tissue-specific accumulation. Neurobiol Dis. 2002;9:139-148.

    Not in our library10.1006/nbdi.2001.0471

  57. 57.

    Wang J, Xu G, Borchelt DR. Mapping superoxide dismutase 1 domains of non-native interaction: roles of intra- and intermolecular disulfide bonding in aggregation. J Neurochem. 2006;96:1277-1288.

    Not in our library10.1111/j.1471-4159.2005.03642.x

  58. 58.

    Durham HD, Roy J, Dong L, Figlewicz DA. Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol. 1997;56:523-530.

    Not in our library10.1097/00005072-199705000-00008

  59. 59.

    Wang J, Slunt H, Gonzales V, Fromholt D, Coonfield M, et al. Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. Hum Mol Genet. 2003;12:2753-2764.

    Not in our library10.1093/hmg/ddg312

  60. 60.

    Stathopulos PB, Rumfeldt JA, Scholz GA, Irani RA, Frey HE, et al. Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc Natl Acad Sci U S A. 2003;100:7021-7026.

    Not in our library10.1073/pnas.1237797100

  61. 61.

    Shaw BF, Lelie HL, Durazo A, Nersissian AM, Xu G, et al. Detergent-insoluble Aggregates Associated with Amyotrophic Lateral Sclerosis in Transgenic Mice Contain Primarily Full-length, Unmodified Superoxide Dismutase-1. J Biol Chem. 2008;283:8340-8350.

    Not in our library10.1074/jbc.m707751200

  62. 62.
    SOD1 and Amyotrophic Lateral Sclerosis: Mutations and Oligomerization · 2008
    No notice
  63. 63.

    Armon C, Moses D. Linear estimates of rates of disease progression as predictors of survival in patients with ALS entering clinical trials. J Neurol Sci. 1998;160:S37-S41.

    Not in our library10.1016/s0022-510x(98)00196-8

  64. 64.

    Czaplinski A, Yen AA, Appel SH. Amyotrophic lateral sclerosis: early predictors of prolonged survival. J Neurol. 2006;253:1428-1436.

    Not in our library10.1007/s00415-006-0226-8

  65. 65.

    Czaplinski A, Yen AA, Simpson EP, Appel SH. Predictability of disease progression in amyotrophic lateral sclerosis. Muscle Nerve. 2006;34:702-708.

    Not in our library10.1002/mus.20658

  66. 66.

    Czaplinski A, Yen AA, Simpson EP, Appel SH. Slower disease progression and prolonged survival in contemporary patients with amyotrophic lateral sclerosis: is the natural history of amyotrophic lateral sclerosis changing. Arch Neurol. 2006;63:1139-1143.

    Not in our library10.1001/archneur.63.8.1139

  67. 67.

    Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41:210-221.

    Not in our library10.1002/ana.410410212

  68. 68.

    Sandelin E, Nordlund A, Andersen PM, Marklund SS, Oliveberg M. Amyotrophic lateral sclerosis-associated copper/zinc superoxide dismutase mutations preferentially reduce the repulsive charge of the proteins. J Biol Chem. 2007;282:21230-21236.

    Not in our library10.1074/jbc.m700765200

  69. 69.

    Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM. Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature. 2003;424:805-808.

    Not in our library10.1038/nature01891

  70. 70.

    Caflisch A. Computational models for the prediction of polypeptide aggregation propensity. Curr Opin Chem Biol. 2006;10:437-444.

    Not in our library10.1016/j.cbpa.2006.07.009

  71. 71.

    Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol. 2004;22:1302-1306.

    Not in our library10.1038/nbt1012

  72. 72.
    Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity · 2007
    No notice
  73. 73.

    DuBay KF, Pawar AP, Chiti F, Zurdo J, Dobson CM, et al. Prediction of the absolute aggregation rates of amyloidogenic polypeptide chains. J Mol Biol. 2004;341:1317-1326.

    Not in our library10.1016/j.jmb.2004.06.043

  74. 74.

    Tartaglia GG, Cavalli A, Pellarin R, Caflisch A. Prediction of aggregation rate and aggregation-prone segments in polypeptide sequences. Protein Sci. 2005;14:2723-2734.

    Not in our library10.1110/ps.051471205

  75. 75.
    Prediction of "hot spots" of aggregation in disease-linked polypeptides · 2005
    No notice
  76. 76.

    Sutedja NA, Veldink JH, Fischer K, Kromhout H, Wokke JH, et al. Lifetime occupation, education, smoking, and risk of ALS. Neurology. 2007;69:1508-1514.

    Not in our library10.1212/01.wnl.0000277463.87361.8c

  77. 77.

    Nelson LM, McGuire V, Longstreth WT, Matkin C. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol. 2000;151:156-163.

    Not in our library10.1093/oxfordjournals.aje.a010183

  78. 78.

    Nelson LM, Matkin C, Longstreth WT, McGuire V. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am J Epidemiol. 2000;151:164-173.

    Not in our library10.1093/oxfordjournals.aje.a010184

  79. 79.

    Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, et al. Nutritional status is a prognostic factor for survival in ALS patients. Neurology. 1999;53:1059-1063.

    Not in our library10.1212/wnl.53.5.1059

  80. 80.

    Kamimoto K, Murakami N, Muroga T, Matsubara M, Yamamoto M. [A comparative study between amyotrophic lateral sclerosis patients with and without mechanical ventilation]. Rinsho Shinkeigaku. 1989;29:989-993.

    Not in our library

  81. 81.

    Perutz MF, Windle AH. Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature. 2001;412:143-144.

    Not in our library10.1038/35084141

  82. 82.

    Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature. 1997;385:787-793.

    Not in our library10.1038/385787a0

  83. 83.

    Fandrich M, Forge V, Buder K, Kittler M, Dobson CM, et al. Myoglobin forms amyloid fibrils by association of unfolded polypeptide segments. Proc Natl Acad Sci U S A. 2003;100:15463-15468.

    Not in our library10.1073/pnas.0303758100

  84. 84.

    Grant MA, Lazo ND, Lomakin A, Condron MM, Arai H, et al. Familial Alzheimer's disease mutations alter the stability of the amyloid beta-protein monomer folding nucleus. Proc Natl Acad Sci U S A. 2007;104:16522-16527.

    Not in our library10.1073/pnas.0705197104

  85. 85.

    Bokvist M, Grobner G. Misfolding of amyloidogenic proteins at membrane surfaces: the impact of macromolecular crowding. J Am Chem Soc. 2007;129:14848-14849.

    Not in our library10.1021/ja076059o

  86. 86.

    Rodriguez JA, Shaw BF, Durazo A, Sohn SH, Doucette PA, et al. Destabilization of apoprotein is insufficient to explain Cu,Zn-superoxide dismutase-linked ALS pathogenesis. Proc Natl Acad Sci U S A. 2005;102:10516-10521.

    Not in our library10.1073/pnas.0502515102

  87. 87.

    Stathopulos PB, Rumfeldt JA, Karbassi F, Siddall CA, Lepock JR, et al. Calorimetric analysis of thermodynamic stability and aggregation for apo and holo amyotrophic lateral sclerosis-associated Gly-93 mutants of superoxide dismutase. J Biol Chem. 2006;281:6184-6193.

    Not in our library10.1074/jbc.m509496200

  88. 88.

    Vassall KA, Stathopulos PB, Rumfeldt JA, Lepock JR, Meiering EM. Equilibrium thermodynamic analysis of amyotrophic lateral sclerosis-associated mutant apo Cu,Zn superoxide dismutases. Biochemistry. 2006;45:7366-7379.

    Not in our library10.1021/bi0600953

  89. 89.

    Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci U S A. 1994;91:8292-8296.

    Not in our library10.1073/pnas.91.17.8292

  90. 90.

    Pellarin R, Caflisch A. Interpreting the aggregation kinetics of amyloid peptides. J Mol Biol. 2006;360:882-892.

    Not in our library10.1016/j.jmb.2006.05.033

  91. 91.

    Kelly JW. Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol. 1996;6:11-17.

    Not in our library10.1016/s0959-440x(96)80089-3

  92. 92.

    Khurana R, Gillespie JR, Talapatra A, Minert LJ, Ionescu-Zanetti C, et al. Partially folded intermediates as critical precursors of light chain amyloid fibrils and amorphous aggregates. Biochemistry. 2001;40:3525-3535.

    Not in our library10.1021/bi001782b

  93. 93.

    DiDonato M, Craig L, Huff ME, Thayer MM, Cardoso RM, et al. ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. J Mol Biol. 2003;332:601-615.

    Not in our library10.1016/s0022-2836(03)00889-1

  94. 94.

    Plakoutsi G, Bemporad F, Calamai M, Taddei N, Dobson CM, et al. Evidence for a mechanism of amyloid formation involving molecular reorganisation within native-like precursor aggregates. J Mol Biol. 2005;351:910-922.

    Not in our library10.1016/j.jmb.2005.06.043

  95. 95.

    Rumfeldt JA, Stathopulos PB, Chakrabarrty A, Lepock JR, Meiering EM. Mechanism and thermodynamics of guanidinium chloride-induced denaturation of ALS-associated mutant Cu,Zn superoxide dismutases. J Mol Biol. 2006;355:106-123.

    Not in our library10.1016/j.jmb.2005.10.042

  96. 96.

    Shaw BF, Durazo A, Nersissian AM, Whitelegge JP, Faull KF, et al. Local unfolding in a destabilized, pathogenic variant of superoxide dismutase 1 observed with H/D exchange and mass spectrometry. J Biol Chem. 2006;281:18167-18176.

    Not in our library10.1074/jbc.m600623200

  97. 97.

    Pawar AP, Dubay KF, Zurdo J, Chiti F, Vendruscolo M, et al. Prediction of “aggregation-prone” and “aggregation-susceptible” regions in proteins associated with neurodegenerative diseases. J Mol Biol. 2005;350:379-392.

    Not in our library10.1016/j.jmb.2005.04.016

  98. 98.

    Fogh I, Rijsdijk F, Andersen PM, Sham PC, Knight J, et al. Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality. Neurogenetics. 2007;8:235-236.

    Not in our library10.1007/s10048-007-0092-2

  99. 99.

    Ivanova M, Jasuja R, Kwong S, Briehl RW, Ferrone FA. Nonideality and the nucleation of sickle hemoglobin. Biophys J. 2000;79:1016-1022.

    Not in our library10.1016/s0006-3495(00)76355-7

  100. 100.

    Christopeit T, Hortschansky P, Schroeckh V, Guhrs K, Zandomeneghi G, et al. Mutagenic analysis of the nucleation propensity of oxidized Alzheimer's beta-amyloid peptide. Protein Sci. 2005;14:2125-2131.

    Not in our library10.1110/ps.051470405

  101. 101.

    Morris AM, Watzky MA, Agar JN, Finke RG. Fitting neurological protein aggregation kinetic data via a 2-step, minimal/“Ockham's razor” model: the Finke–Watzky mechanism of nucleation followed by autocatalytic surface growth. Biochemistry. 2008;47:2413-2427.

    Not in our library10.1021/bi701899y

  102. 102.

    Sjalander A, Beckman G, Deng HX, Iqbal Z, Tainer JA, et al. The D90A mutation results in a polymorphism of Cu,Zn superoxide dismutase that is prevalent in northern Sweden and Finland. Hum Mol Genet. 1995;4:1105-1108.

    Not in our library10.1093/hmg/4.6.1105

  103. 103.

    Robberecht W, Aguirre T, Van den Bosch L, Tilkin P, Cassiman JJ, et al. D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. Neurology. 1996;47:1336-1339.

    Not in our library10.1212/wnl.47.5.1336

  104. 104.

    O'Nuallain B, Thakur AK, Williams AD, Bhattacharyya AM, Chen S, et al. Kinetics and thermodynamics of amyloid assembly using a high-performance liquid chromatography-based sedimentation assay. Methods Enzymol. 2006;413:34-74.

    Not in our library10.1016/s0076-6879(06)13003-7

  105. 105.

    Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, et al. Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet. 2007;16:1604-1618.

    Not in our library10.1093/hmg/ddm110

  106. 106.

    Ross CA, Poirier MA. Opinion: what is the role of protein aggregation in neurodegeneration. Nat Rev Mol Cell Biol. 2005;6:891-898.

    Not in our library10.1038/nrm1742

  107. 107.

    Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267-298.

    Not in our library10.1146/annurev.neuro.26.010302.081142

  108. 108.

    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002;416:507-511.

    Not in our library10.1038/416507a

  109. 109.

    Taylor DM, Gibbs BF, Kabashi E, Minotti S, Durham HD, et al. Tryptophan 32 potentiates aggregation and cytotoxicity of a copper/zinc superoxide dismutase mutant associated with familial amyotrophic lateral sclerosis. J Biol Chem. 2007;282:16329-16335.

    Not in our library10.1074/jbc.m610119200

  110. 110.

    Witan H, Kern A, Koziollek-Drechsler I, Wade R, Behl C, et al. Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-Superoxide dismutase induces toxicity independent of protein aggregation. Hum Mol Genet. 2008;17:1373-1385.

    Not in our library10.1093/hmg/ddn025

  111. 111.

    Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004;431:805-810.

    Not in our library10.1038/nature02998

  112. 112.

    Stefani M, Dobson CM. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med. 2003;81:678-699.

    Not in our library10.1007/s00109-003-0464-5

  113. 113.

    Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, et al. Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol. 1996;55:481-490.

    Not in our library10.1097/00005072-199604000-00011

  114. 114.

    Shibata N, Asayama K, Hirano A, Kobayashi M. Immunohistochemical study on superoxide dismutases in spinal cords from autopsied patients with amyotrophic lateral sclerosis. Dev Neurosci. 1996;18:492-498.

    Not in our library10.1159/000111445

  115. 115.

    Wood JD, Beaujeux TP, Shaw PJ. Protein aggregation in motor neurone disorders. Neuropathol Appl Neurobiol. 2003;29:529-545.

    Not in our library10.1046/j.0305-1846.2003.00518.x

  116. 116.
    Fibrillar Inclusions and Motor Neuron Degeneration in Transgenic Mice Expressing Superoxide Dismutase 1 with a Disrupted Copper-Binding Site · 2002
    Not checked
  117. 117.

    Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997;18:327-338.

    Not in our library10.1016/s0896-6273(00)80272-x

  118. 118.

    Watanabe Y, Yasui K, Nakano T, Doi K, Fukada Y, et al. Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification. Brain Res Mol Brain Res. 2005;135:12-20.

    Not in our library10.1016/j.molbrainres.2004.11.019

  119. 119.

    Jonsson PA, Ernhill K, Andersen PM, Bergemalm D, Brannstrom T, et al. Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. Brain. 2004;127:73-88.

    Not in our library10.1093/brain/awh005

  120. 120.

    Chang-Hong R, Wada M, Koyama S, Kimura H, Arawaka S, et al. Neuroprotective effect of oxidized galectin-1 in a transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2005;194:203-211.

    Not in our library10.1016/j.expneurol.2005.02.011

  121. 121.

    Tobisawa S, Hozumi Y, Arawaka S, Koyama S, Wada M, et al. Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Biochem Biophys Res Commun. 2003;303:496-503.

    Not in our library10.1016/s0006-291x(03)00353-x

  122. 122.

    Jonsson PA, Bergemalm D, Andersen PM, Gredal O, Brannstrom T, et al. Inclusions of amyotrophic lateral sclerosis-linked superoxide dismutase in ventral horns, liver, and kidney. Ann Neurol. 2008;63:671-675.

    Not in our library10.1002/ana.21356

  123. 123.

    Zetterstrom P, Stewart HG, Bergemalm D, Jonsson PA, Graffmo KS, et al. Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models. Proc Natl Acad Sci U S A. 2007;104:14157-14162.

    Not in our library10.1073/pnas.0700477104

  124. 124.

    Jonsson PA, Graffmo KS, Brannstrom T, Nilsson P, Andersen PM, et al. Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1. J Neuropathol Exp Neurol. 2006;65:1126-1136.

    Not in our library10.1097/01.jnen.0000248545.36046.3c

  125. 125.

    Wang J, Xu G, Li H, Gonzales V, Fromholt D, et al. Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: αB-crystallin modulates aggregation. Hum Mol Genet. 2005;14:2335-2347.

    Not in our library10.1093/hmg/ddi236

  126. 126.

    Gurney ME. The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J Neurol Sci. 1997;152:S67-S73.

    Not in our library10.1016/s0022-510x(97)00247-5

  127. 127.

    Nagai M, Aoki M, Miyoshi I, Kato M, Pasinelli P, et al. Rats expressing human cytosolic copper–zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. J Neurosci. 2001;21:9246-9254.

    Not in our library10.1523/jneurosci.21-23-09246.2001

  128. 128.

    Howland DS, Liu J, She Y, Goad B, Maragakis NJ, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002;99:1604-1609.

    Not in our library10.1073/pnas.032539299

  129. 129.

    Johnston JA, Dalton MJ, Gurney ME, Kopito RR. Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2000;97:12571-12576.

    Not in our library10.1073/pnas.220417997

  130. 130.

    Shinder GA, Lacourse MC, Minotti S, Durham HD. Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis. J Biol Chem. 2001;276:12791-12796.

    Not in our library10.1074/jbc.m010759200

  131. 131.

    Wang J, Xu G, Slunt HH, Gonzales V, Coonfield M, et al. Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA. Neurobiol Dis. 2005;20:943-952.

    Not in our library10.1016/j.nbd.2005.06.005

  132. 132.

    Allgulander C, Fisher LD. Survival analysis (or time to an event analysis), and the Cox regression model—methods for longitudinal psychiatric research. Acta Psychiatr Scand. 1986;74:529-535.

    Not in our library10.1111/j.1600-0447.1986.tb06279.x

  133. 133.

    Chiti F, Calamai M, Taddei N, Stefani M, Ramponi G, et al. Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases. Proc Natl Acad Sci U S A. 2002;99:16419-16426.

    Not in our library10.1073/pnas.212527999

  134. 134.

    Azriel R, Gazit E. Analysis of the minimal amyloid-forming fragment of the islet amyloid polypeptide. An experimental support for the key role of the phenylalanine residue in amyloid formation. J Biol Chem. 2001;276:34156-34161.

    Not in our library10.1074/jbc.m102883200

  135. 135.

    Sakagashira S, Hiddinga HJ, Tateishi K, Sanke T, Hanabusa T, et al. S20G mutant amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin. Am J Pathol. 2000;157:2101-2109.

    Not in our library10.1016/s0002-9440(10)64848-1

  136. 136.

    Salmona M, Malesani P, De Gioia L, Gorla S, Bruschi M, et al. Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106–126. Biochem J. 1999;342:207-214.

    Not in our library

  137. 137.

    Thompson AJ, Barnham KJ, Norton RS, Barrow CJ. The Val-210-Ile pathogenic Creutzfeldt-Jakob disease mutation increases both the helical and aggregation propensities of a sequence corresponding to helix-3 of PrPC. Biochim Biophys Acta. 2001;1544:242-254.

    Not in our library10.1016/s0167-4838(00)00225-9

  138. 138.
    Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: Implications for pathogenesis and therapy · 2000
    Not checked
  139. 139.

    Giasson BI, Murray IV, Trojanowski JQ, Lee VM. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J Biol Chem. 2001;276:2380-2386.

    Not in our library10.1074/jbc.m008919200

  140. 140.

    Van Nostrand WE, Melchor JP, Cho HS, Greenberg SM, Rebeck GW. Pathogenic effects of D23N Iowa mutant amyloid β -protein. J Biol Chem. 2001;276:32860-32866.

    Not in our library10.1074/jbc.m104135200

  141. 141.

    Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, et al. Substitutions at codon 22 of Alzheimer's Aβ peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000;275:27110-27116.

    Not in our library10.1074/jbc.m003154200

  142. 142.

    Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, et al. The ‘Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation. Nat Neurosci. 2001;4:887-893.

    Not in our library10.1038/nn0901-887

  143. 143.

    Esler WP, Stimson ER, Ghilardi JR, Lu YA, Felix AM, et al. Point substitution in the central hydrophobic cluster of a human β-amyloid congener disrupts peptide folding and abolishes plaque competence. Biochemistry. 1996;35:13914-13921.

    Not in our library10.1021/bi961302+

  144. 144.

    Gamblin TC, Berry RW, Binder LI. Tau polymerization: role of the amino terminus. Biochemistry. 2003;42:2252-2257.

    Not in our library10.1021/bi0272510

  145. 145.

    Barghorn S, Zheng-Fischhofer Q, Ackmann M, Biernat J, von Bergen M, et al. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000;39:11714-11721.

    Not in our library10.1021/bi000850r

  146. 146.

    Gamblin TC, King ME, Dawson H, Vitek MP, Kuret J, et al. In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochemistry. 2000;39:6136-6144.

    Not in our library10.1021/bi000201f

  147. 147.

    Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, et al. Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999;447:195-199.

    Not in our library10.1016/s0014-5793(99)00294-x

  148. 148.

    Li L, von Bergen M, Mandelkow EM, Mandelkow E. Structure, stability, and aggregation of paired helical filaments from tau protein and FTDP-17 mutants probed by tryptophan scanning mutagenesis. J Biol Chem. 2002;277:41390-41400.

    Not in our library10.1074/jbc.m206334200

  149. 149.

    Symmons MF, Buchanan SG, Clarke DT, Jones G, Gay NJ. X-ray diffraction and far-UV CD studies of filaments formed by a leucine-rich repeat peptide: structural similarity to the amyloid fibrils of prions and Alzheimer's disease β-protein. FEBS Lett. 1997;412:397-403.

    Not in our library10.1016/s0014-5793(97)00809-0

  150. 150.

    Orpiszewski J, Benson MD. Induction of β-sheet structure in amyloidogenic peptides by neutralization of aspartate: a model for amyloid nucleation. J Mol Biol. 1999;289:413-428.

    Not in our library10.1006/jmbi.1999.2768

  151. 151.

    Wirehn J, Carlsson K, Herland A, Persson E, Carlsson U, et al. Activity, folding, misfolding, and aggregation in vitro of the naturally occurring human tissue factor mutant R200W. Biochemistry. 2005;44:6755-6763.

    Not in our library10.1021/bi047388l

  152. 152.

    Hammarstrom P, Sekijima Y, White JT, Wiseman RL, Lim A, et al. D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis. Biochemistry. 2003;42:6656-6663.

    Not in our library10.1021/bi027319b

  153. 153.

    Kenig M, Berbic S, Krijestorac A, Kroon-Zitko L, Tusek M, et al. Differences in aggregation properties of three site-specific mutants of recombinant human stefin B. Protein Sci. 2004;13:63-70.

    Not in our library10.1110/ps.03270904

  154. 154.

    Du HN, Tang L, Luo XY, Li HT, Hu J, et al. A peptide motif consisting of glycine, alanine, and valine is required for the fibrillization and cytotoxicity of human α-synuclein. Biochemistry. 2003;42:8870-8878.

    Not in our library10.1021/bi034028+

  155. 155.

    Parrini C, Taddei N, Ramazzotti M, Degl'Innocenti D, Ramponi G, et al. Glycine residues appear to be evolutionarily conserved for their ability to inhibit aggregation. Structure. 2005;13:1143-1151.

    Not in our library10.1016/j.str.2005.04.022

  156. 156.

    Sato T, Nakanishi T, Yamamoto Y, Andersen PM, Ogawa Y, et al. Rapid disease progression correlates with instability of mutant SOD1 in familial ALS. Neurology. 2005;65:1954-1957.

    Not in our library10.1212/01.wnl.0000188760.53922.05

  157. 157.

    Aksoy H, Dean G, Elian M, Deng HX, Deng G, et al. A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. Neuroepidemiology. 2003;22:235-238.

    Not in our library10.1159/000070564

  158. 158.

    Juneja T, Pericak-Vance MA, Laing NG, Dave S, Siddique T. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with Glu100Gly and Ala4Val mutations in Cu,Zn superoxide dismutase. Neurology. 1997;48:55-57.

    Not in our library10.1212/wnl.48.1.55

  159. 159.

    Nakano R, Sato S, Inuzuka T, Sakimura K, Mishina M, et al. A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 1994;200:695-703.

    Not in our library10.1006/bbrc.1994.1506

  160. 160.

    Cudkowicz ME, McKenna-Yasek D, Chen C, Hedley-Whyte ET, Brown RH. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. Ann Neurol. 1998;43:703-710.

    Not in our library10.1002/ana.410430604

  161. 161.

    Rosen DR, Bowling AC, Patterson D, Usdin TB, Sapp P, et al. A frequent Ala 4 to Val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis. Hum Mol Genet. 1994;3:981-987.

    Not in our library10.1093/hmg/3.6.981

  162. 162.

    Andersen PM, Nilsson P, Keranen ML, Forsgren L, Hagglund J, et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain. 1997;120:1723-1737.

    Not in our library10.1093/brain/120.10.1723

  163. 163.

    Gellera C, Castellotti B, Riggio MC, Silani V, Morandi L, et al. Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations. Neuromuscul Disord. 2001;11:404-410.

    Not in our library10.1016/s0960-8966(00)00215-7

  164. 164.

    Andersen PM, Sims KB, Xin WW, Kiely R, O'Neill G, et al. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:62-73.

    Not in our library10.1080/14660820310011700

  165. 165.

    Stewart HG, Andersen PM, Eisen A, Weber M. Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations. Clin Neurophysiol. 2006;117:1850-1861.

    Not in our library10.1016/j.clinph.2006.04.004

  166. 166.

    Kohno S, Takahashi Y, Miyajima H, Serizawa M, Mizoguchi K. A novel mutation (Cys6Gly) in the Cu/Zn superoxide dismutase gene associated with rapidly progressive familial amyotrophic lateral sclerosis. Neurosci Lett. 1999;276:135-137.

    Not in our library10.1016/s0304-3940(99)00803-4

  167. 167.

    Morita M, Aoki M, Abe K, Hasegawa T, Sakuma R, et al. A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. Neurosci Lett. 1996;205:79-82.

    Not in our library10.1016/0304-3940(96)12378-8

  168. 168.

    Hirano M, Fujii J, Nagai Y, Sonobe M, Okamoto K, et al. A new variant Cu/Zn superoxide dismutase (Val7→Glu) deduced from lymphocyte mRNA sequences from Japanese patients with familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 1994;204:572-577.

    Not in our library10.1006/bbrc.1994.2497

  169. 169.

    Bereznai B, Winkler A, Borasio GD, Gasser T. A novel SOD1 mutation in an Austrian family with amyotrophic lateral sclerosis. Neuromuscul Disord. 1997;7:113-116.

    Not in our library10.1016/s0960-8966(96)00419-1

  170. 170.

    Kim NH, Kim HJ, Kim M, Lee KW. A novel SOD1 gene mutation in a Korean family with amyotrophic lateral sclerosis. J Neurol Sci. 2003;206:65-69.

    Not in our library10.1016/s0022-510x(02)00338-6

  171. 171.

    Penco S, Schenone A, Bordo D, Bolognesi M, Abbruzzese M, et al. A SOD1 gene mutation in a patient with slowly progressing familial ALS. Neurology. 1999;53:404-406.

    Not in our library10.1212/wnl.53.2.404

  172. 172.

    Battistini S, Giannini F, Greco G, Bibbo G, Ferrera L, et al. SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. J Neurol. 2005;252:782-788.

    Not in our library10.1007/s00415-005-0742-y

  173. 173.

    Gellera C. Genetics of ALS in Italian families. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001;2:S43-S46.

    Not in our library10.1080/14660820152415735

  174. 174.

    Kim HY, Ki CS, Koh SH, Park KH, Sunwoo IN, et al. Clinical characteristics of familial amyotrophic lateral sclerosis with a Phe20Cys mutation in the SOD1 gene in a Korean family. Amyotroph Lateral Scler. 2007;8:73-78.

    Not in our library10.1080/17482960701223154

  175. 175.

    Jafari-Schluep HF, Khoris J, Mayeux-Portas V, Hand C, Rouleau G, et al. [Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature]. Rev Neurol (Paris). 2004;160:44-50.

    Not in our library10.1016/s0035-3787(04)70846-2

  176. 176.

    Camu W, Khoris J, Moulard B, Salachas F, Briolotti V, et al. Genetics of familial ALS and consequences for diagnosis. French ALS Research Group. J Neurol Sci. 1999;165:S21-S26.

    Not in our library10.1016/s0022-510x(99)00022-2

  177. 177.

    Inoue K, Fujimura H, Ogawa Y, Satoh T, Shimada K, et al. Familial amyotrophic lateral sclerosis with a point mutation (G37R) of the superoxide dismutase 1 gene: a clinicopathological study. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002;3:244-247.

    Not in our library10.1080/146608202760839012

  178. 178.

    Gamez J, Corbera-Bellalta M, Nogales G, Raguer N, Garcia-Arumi E, et al. Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1. J Neurol Sci. 2006;247:21-28.

    Not in our library10.1016/j.jns.2006.03.006

  179. 179.

    Garcia-Redondo A, Bustos F, Juan YSB, Del Hoyo P, Jimenez S, et al. Molecular analysis of the superoxide dismutase 1 gene in Spanish patients with sporadic or familial amyotrophic lateral sclerosis. Muscle Nerve. 2002;26:274-278.

    Not in our library10.1002/mus.10193

  180. 180.

    Regal L, Vanopdenbosch L, Tilkin P, Van den Bosch L, Thijs V, et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch Neurol. 2006;63:262-267.

    Not in our library10.1001/archneur.63.2.262

  181. 181.

    Rainero I, Pinessi L, Tsuda T, Vignocchi MG, Vaula G, et al. SOD1 missense mutation in an Italian family with ALS. Neurology. 1994;44:347-349.

    Not in our library10.1212/wnl.44.2.347

  182. 182.

    Arisato T, Okubo R, Arata H, Abe K, Fukada K, et al. Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families. Acta Neuropathol. 2003;106:561-568.

    Not in our library10.1007/s00401-003-0763-5

  183. 183.

    Ohi T, Nabeshima K, Kato S, Yazawa S, Takechi S. Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions. J Neurol Sci. 2004;225:19-25.

    Not in our library10.1016/j.jns.2004.06.008

  184. 184.

    Ohi T, Saita K, Takechi S, Nabesima K, Tashiro H, et al. Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase. J Neurol Sci. 2002;197:73-78.

    Not in our library10.1016/s0022-510x(02)00054-0

  185. 185.

    Aoki M, Abe K, Itoyama Y. Molecular analyses of the Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS) in Japan. Cell Mol Neurobiol. 1998;18:639-647.

    Not in our library10.1023/a:1020681802277

  186. 186.

    Holmoy T, Bjorgo K, Roos PM. Slowly progressing amyotrophic lateral sclerosis caused by H46R SOD1 mutation. Eur Neurol. 2007;58:57-58.

    Not in our library10.1159/000102170

  187. 187.

    Shaw CE, Enayat ZE, Powell JF, Anderson VE, Radunovic A, et al. Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation. Neurology. 1997;49:1612-1616.

    Not in our library10.1212/wnl.49.6.1612

  188. 188.

    Orrell RW, Habgood JJ, Gardiner I, King AW, Bowe FA, et al. Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. Neurology. 1997;48:746-751.

    Not in our library10.1212/wnl.48.3.746

  189. 189.

    Stewart HG, Mackenzie IR, Eisen A, Brannstrom T, Marklund SL, et al. Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy. Muscle Nerve. 2006;33:701-706.

    Not in our library10.1002/mus.20495

  190. 190.

    Orrell RW, Marklund SL, deBelleroche JS. Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser). J Neurol Sci. 1997;153:46-49.

    Not in our library10.1016/s0022-510x(97)00181-0

  191. 191.

    Segovia-Silvestre T, Andreu AL, Vives-Bauza C, Garcia-Arumi E, Cervera C, et al. A novel exon 3 mutation (D76V) in the SOD1 gene associated with slowly progressive ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002;3:69-74.

    Not in our library10.1080/146608202760196039

  192. 192.

    Ceroni M, Malaspina A, Poloni TE, Alimonti D, Rognoni F, et al. Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation. Neurology. 1999;53:1064-1071.

    Not in our library10.1212/wnl.53.5.1064

  193. 193.

    Shaw CE, Enayat ZE, Chioza BA, Al-Chalabi A, Radunovic A, et al. Mutations in all five exons of SOD-1 may cause ALS. Ann Neurol. 1998;43:390-394.

    Not in our library10.1002/ana.410430319

  194. 194.

    Curti D, Rognoni F, Alimonti D, Malaspina A, Feletti F, et al. SOD1 activity and protective factors in familial ALS patients with L84F SOD1 mutation. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002;3:115-122.

    Not in our library10.1080/146608202760834111

  195. 195.

    Ohnishi A, Miyazaki S, Murai Y, Ueno S, Sakai H. [Familial amyotrophic lateral sclerosis showing variable clinical courses with (Leu84→Val) mutation of Cu/Zn superoxide dismutase]. Rinsho Shinkeigaku. 1996;36:485-487.

    Not in our library

  196. 196.

    Beck M, Sendtner M, Toyka KV. Novel SOD1 N86K mutation is associated with a severe phenotype in familial ALS. Muscle Nerve. 2007;36:111-114.

    Not in our library10.1002/mus.20756

  197. 197.

    Maeda T, Kurahashi K, Matsunaga M, Inoue K, Inoue M. [On intra-familial clinical diversities of a familial amyotrophic lateral sclerosis with a point mutation of Cu/Zn superoxide dismutase (Asn 86-Ser)]. No To Shinkei. 1997;49:847-851.

    Not in our library

  198. 198.

    Rezania K, Yan J, Dellefave L, Deng HX, Siddique N, et al. A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset, incomplete penetrance and a sensory neuropathy. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:162-166.

    Not in our library10.1080/aml.4.3.162.166

  199. 199.

    Khoris J, Moulard B, Briolotti V, Hayer M, Durieux A, et al. Coexistence of dominant and recessive familial amyotrophic lateral sclerosis with the D90A Cu,Zn superoxide dismutase mutation within the same country. Eur J Neurol. 2000;7:207-211.

    Not in our library10.1046/j.1468-1331.2000.00028.x

  200. 200.

    Morita M, Abe K, Takahashi M, Onodera Y, Okumura H, et al. A novel mutation Asp90Val in the SOD1 gene associated with Japanese familial ALS. Eur J Neurol. 1998;5:389-392.

    Not in our library

  201. 201.

    Esteban J, Rosen DR, Bowling AC, Sapp P, McKenna-Yasek D, et al. Identification of two novel mutations and a new polymorphism in the gene for Cu/Zn superoxide dismutase in patients with amyotrophic lateral sclerosis. Hum Mol Genet. 1994;3:997-998.

    Not in our library10.1093/hmg/3.6.997

  202. 202.

    Kawata A, Kato S, Hayashi H, Hirai S. Prominent sensory and autonomic disturbances in familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene. J Neurol Sci. 1997;153:82-85.

    Not in our library10.1016/s0022-510x(97)00176-7

  203. 203.

    Iwai K, Yamamoto M, Yoshihara T, Sobue G. Anticipation in familial amyotrophic lateral sclerosis with SOD1-G93S mutation. J Neurol Neurosurg Psychiatry. 2002;72:819-820.

    Not in our library10.1136/jnnp.72.6.819

  204. 204.

    Hosler BA, Nicholson GA, Sapp PC, Chin W, Orrell RW, et al. Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis. Neuromuscul Disord. 1996;6:361-366.

    Not in our library10.1016/0960-8966(96)00353-7

  205. 205.

    Ince PG, Shaw PJ, Slade JY, Jones C, Hudgson P. Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes. Acta Neuropathol. 1996;92:395-403.

    Not in our library10.1007/s004010050535

  206. 206.

    Cervenakova L, Protas II, Hirano A, Votiakov VI, Nedzved MK, et al. Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS). J Neurol Sci. 2000;177:124-130.

    Not in our library10.1016/s0022-510x(00)00350-6

  207. 207.

    Orrell RW, Habgood J, Rudge P, Lane RJ, de Belleroche JS. Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis. Ann Neurol. 1996;39:810-812.

    Not in our library10.1002/ana.410390620

  208. 208.

    Orrell RW, Habgood JJ, Malaspina A, Mitchell J, Greenwood J, et al. Clinical characteristics of SOD1 gene mutations in UK families with ALS. J Neurol Sci. 1999;169:56-60.

    Not in our library10.1016/s0022-510x(99)00216-6

  209. 209.

    Sato T, Yamamoto Y, Nakanishi T, Fukada K, Sugai F, et al. Identification of two novel mutations in the Cu/Zn superoxide dismutase gene with familial amyotrophic lateral sclerosis: mass spectrometric and genomic analyses. J Neurol Sci. 2004;218:79-83.

    Not in our library10.1016/j.jns.2003.11.003

  210. 210.

    Tan CF, Piao YS, Hayashi S, Obata H, Umeda Y, et al. Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation. Acta Neuropathol. 2004;108:332-336.

    Not in our library10.1007/s00401-004-0893-4

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    Abe K. Clinical and molecular analysis of neurodegenerative diseases. Tohoku J Exp Med. 1997;181:389-409.

    Not in our library10.1620/tjem.181.389

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    Zhang H, Zhao H, Lu M, Zhang Y, Wang L, et al. A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset and incomplete penetrance in China. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005;6:234-238.

    Not in our library10.1080/14660820510044478

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    Orrell RW, Habgood JJ, Shepherd DI, Donnai D, deBelleroche JS. A novel mutation of SOD-1 (Gly 108 Val) in familial amyotrophic lateral sclerosis. Eur J Neurol. 1997;4:48-51.

    Not in our library10.1111/j.1468-1331.1997.tb00298.x

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    Rouleau GA, Clark AW, Rooke K, Pramatarova A, Krizus A, et al. SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. Ann Neurol. 1996;39:128-131.

    Not in our library10.1002/ana.410390119

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    Kokubo Y, Kuzuhara S, Narita Y, Kikugawa K, Nakano R, et al. Accumulation of neurofilaments and SOD1-immunoreactive products in a patient with familial amyotrophic lateral sclerosis with I113T SOD1 mutation. Arch Neurol. 1999;56:1506-1508.

    Not in our library10.1001/archneur.56.12.1506

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    Jones CT, Swingler RJ, Simpson SA, Brock DJ. Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients. J Med Genet. 1995;32:290-292.

    Not in our library10.1136/jmg.32.4.290

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    Ince PG, Tomkins J, Slade JY, Thatcher NM, Shaw PJ. Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS. J Neuropathol Exp Neurol. 1998;57:895-904.

    Not in our library10.1097/00005072-199810000-00002

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    Suthers G, Laing N, Wilton S, Dorosz S, Waddy H. “Sporadic” motoneuron disease due to familial SOD1 mutation with low penetrance. Lancet. 1994;344:1773.

    Not in our library10.1016/s0140-6736(94)92913-0

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    Kostrzewa M, Burck-Lehmann U, Muller U. Autosomal dominant amyotrophic lateral sclerosis: a novel mutation in the Cu/Zn superoxide dismutase-1 gene. Hum Mol Genet. 1994;3:2261-2262.

    Not in our library10.1093/hmg/3.12.2261

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    Enayat ZE, Orrell RW, Claus A, Ludolph A, Bachus R, et al. Two novel mutations in the gene for copper zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. Hum Mol Genet. 1995;4:1239-1240.

    Not in our library10.1093/hmg/4.7.1239

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    Takehisa Y, Ujike H, Ishizu H, Terada S, Haraguchi T, et al. Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions. Arch Neurol. 2001;58:736-740.

    Not in our library10.1001/archneur.58.5.736

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    Murakami T, Warita H, Hayashi T, Sato K, Manabe Y, et al. A novel SOD1 gene mutation in familial ALS with low penetrance in females. J Neurol Sci. 2001;189:45-47.

    Not in our library10.1016/s0022-510x(01)00558-5

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    Watanabe M, Aoki M, Abe K, Shoji M, Iizuka T, et al. A novel missense point mutation (S134N) of the Cu/Zn superoxide dismutase gene in a patient with familial motor neuron disease. Hum Mutat. 1997;9:69-71.

    Not in our library10.1002/(sici)1098-1004(1997)9:1<69::aid-humu14>3.0.co;2-n

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    Nogales-Gadea G, Garcia-Arumi E, Andreu AL, Cervera C, Gamez J. A novel exon 5 mutation (N139H) in the SOD1 gene in a Spanish family associated with incomplete penetrance. J Neurol Sci. 2004;219:1-6.

    Not in our library10.1016/j.jns.2003.10.018

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    Naini A, Musumeci O, Hayes L, Pallotti F, Del Bene M, et al. Identification of a novel mutation in Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis. J Neurol Sci. 2002;198:17-19.

    Not in our library10.1016/s0022-510x(02)00052-7

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    Mase G, Ros S, Gemma A, Bonfigli L, Carraro N, et al. ALS with variable phenotypes in a six-generation family caused by Leu144Phe mutation in the SOD1 gene. J Neurol Sci. 2001;191:11-18.

    Not in our library10.1016/s0022-510x(01)00625-6

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    Ferrera L, Caponnetto C, Marini V, Rizzi D, Bordo D, et al. An Italian dominant FALS Leu144Phe SOD1 mutation: genotype-phenotype correlation. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:167-170.

    Not in our library10.1080/aml.4.3.167.170

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    Ito K, Uchiyama T, Fukutake T, Arai K, Kanesaka T, et al. [Different clinical phenotypes of siblings with familial amyotrophic lateral sclerosis showing Cys146Arg point mutation of superoxide dismutase 1 gene]. Rinsho Shinkeigaku. 2002;42:175-177.

    Not in our library

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    Fong GC, Kwok KH, Song YQ, Cheng TS, Ho PW, et al. Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation. Amyotroph Lateral Scler. 2006;7:142-149.

    Not in our library10.1080/17482960600732412

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    Kostrzewa M, Damian MS, Muller U. Superoxide dismutase 1: identification of a novel mutation in a case of familial amyotrophic lateral sclerosis. Hum Genet. 1996;98:48-50.

    Not in our library10.1007/s004390050157

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