Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

Abstract

Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the RNA-binding protein TDP-43, is hyperphosphorylated in disease on several C-terminal serine residues, which is generally believed to promote TDP-43 aggregation. Here, we show that hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduce TDP-43 phase separation and aggregation and render TDP-43 condensates more liquid-like and dynamic. Multi-scale simulations reveal reduced homotypic interactions of TDP-43 low complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We propose that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

References 86

1. 1.

   Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015 ) GROMACS: high performance molecular simulations through multi‐level parallelism from laptops to supercomputers. SoftwareX 1–2: 19–25

   Not in our library

2. 2.
   Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation · 2017

   No notice
3. 3.

   Alberti S (2017 ) Phase separation in biology. Curr Biol 27: R1097–R1102

   Not in our library10.1016/j.cub.2017.08.069

4. 4.

   Alberti S, Dormann D (2019 ) Liquid‐liquid phase separation in disease. Annu Rev Genet 53: 171–194

   Not in our library10.1146/annurev-genet-112618-043527

5. 5.

   Alberti S, Hyman AA (2021 ) Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol 22: 196–213

   Not in our library10.1038/s41580-020-00326-6

6. 6.
   Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation · 2021

   No notice
7. 7.

   Avendano‐Vazquez SE, Dhir A, Bembich S, Buratti E, Proudfoot N, Baralle FE (2012 ) Autoregulation of TDP‐43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev 26: 1679–1684

   Not in our library10.1101/gad.194829.112

8. 8.

   Ayala YM, De Conti L, Avendaño‐Vázquez SE, Dhir A, Romano M, D'Ambrogio A, Tollervey J, Ule J, Baralle M, Buratti E et al (2011 ) TDP‐43 regulates its mRNA levels through a negative feedback loop. EMBO J 30: 277–288

   Not in our library10.1038/emboj.2010.310

9. 9.

   Babinchak WM, Haider R, Dumm BK, Sarkar P, Surewicz K, Choi JK, Surewicz WK (2019 ) The role of liquid‐liquid phase separation in aggregation of the TDP‐43 low‐complexity domain. J Biol Chem 294: 6306–6317

   Not in our library10.1074/jbc.ra118.007222

10. 10.

    Bah A, Forman‐Kay JD (2016 ) Modulation of intrinsically disordered protein function by post‐translational modifications. J Biol Chem 291: 6696–6705

    Not in our library10.1074/jbc.r115.695056

11. 11.

    Benayad Z, von Bulow S, Stelzl LS, Hummer G (2021 ) Simulation of FUS protein condensates with an adapted coarse‐grained model. J Chem Theory Comput 17: 525–537

    Not in our library10.1021/acs.jctc.0c01064

12. 12.
    The mutational landscape of a prion-like domain · 2019

    No notice
13. 13.

    Brady OA, Meng P, Zheng Y, Mao Y, Hu F (2011 ) Regulation of TDP‐43 aggregation by phosphorylation and p62/SQSTM1. J Neurochem 116: 248–259

    Not in our library10.1111/j.1471-4159.2010.07098.x

14. 14.

    Bremer A, Farag M, Borcherds WM, Peran I, Martin EW, Pappu RV, Mittag T (2021 ) Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion‐like domains. bioRxiv [PREPRINT]

    Not in our library10.1101/2021.01.01.425046

15. 15.

    Buratti E (2015 ) Functional significance of TDP‐43 mutations in disease. Adv Genet 91: 1–53

    Not in our library10.1016/bs.adgen.2015.07.001

16. 16.

    Buratti E (2018 ) TDP‐43 post‐translational modifications in health and disease. Expert Opin Ther Targets 22: 279–293

    Not in our library10.1080/14728222.2018.1439923

17. 17.

    Bussi G, Donadio D, Parrinello M (2007 ) Canonical sampling through velocity rescaling. J Chem Phys 126: 014101

    Not in our library10.1063/1.2408420

18. 18.

    Ceballos AV, McDonald CJ, Elbaum‐Garfinkle S (2018 ) Methods and strategies to quantify phase separation of disordered proteins. Methods Enzymol 611: 31–50

    Not in our library10.1016/bs.mie.2018.09.037

19. 19.

    Choksi DK, Roy B, Chatterjee S, Yusuff T, Bakhoum MF, Sengupta U, Ambegaokar S, Kayed R, Jackson GR (2014 ) TDP‐43 Phosphorylation by casein kinase Iepsilon promotes oligomerization and enhances toxicity in vivo. Hum Mol Genet 23: 1025–1035

    Not in our library10.1093/hmg/ddt498

20. 20.

    Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016 ) ALS mutations disrupt phase separation mediated by alpha‐helical structure in the TDP‐43 low‐complexity C‐terminal domain. Structure 24: 1537–1549

    Not in our library10.1016/j.str.2016.07.007

21. 21.

    Conicella AE, Dignon GL, Zerze GH, Schmidt HB, D'Ordine AM, Kim YC, Rohatgi R, Ayala YM, Mittal J, Fawzi NL (2020 ) TDP‐43 alpha‐helical structure tunes liquid‐liquid phase separation and function. Proc Natl Acad Sci USA 117: 5883–5894

    Not in our library10.1073/pnas.1912055117

22. 22.

    Crabtree MD, Holland J, Kompella P, Babl L, Turner N, Baldwin AJ (2020 ) Repulsive electrostatic interactions modulate dense and dilute phase properties of biomolecular condensates. bioRxiv [PREPRINT]

    Not in our library10.1101/2020.10.29.357863

23. 23.
    Sequence determinants of protein phase behavior from a coarse-grained model · 2018

    No notice
24. 24.

    Dormann D, Capell A, Carlson AM, Shankaran SS, Rodde R, Neumann M, Kremmer E, Matsuwaki T, Yamanouchi K, Nishihara M et al (2009 ) Proteolytic processing of TAR DNA binding protein‐43 by caspases produces C‐terminal fragments with disease defining properties independent of progranulin. J Neurochem 110: 1082–1094

    Not in our library10.1111/j.1471-4159.2009.06211.x

25. 25.

    Durocher D, Henckel J, Fersht AR, Jackson SP (1999 ) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4: 387–394

    Not in our library10.1016/s1097-2765(00)80340-8

26. 26.
    Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1 · 2018

    No notice
27. 27.

    Fiesel FC, Weber SS, Supper J, Zell A, Kahle PJ (2012 ) TDP‐43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucleic Acids Res 40: 2668–2682

    Not in our library10.1093/nar/gkr1082

28. 28.

    French RL, Grese ZR, Aligireddy H, Dhavale DD, Reeb AN, Kedia N, Kotzbauer PT, Bieschke J, Ayala YM (2019 ) Detection of TAR DNA‐binding protein 43 (TDP‐43) oligomers as initial intermediate species during aggregate formation. J Biol Chem 294: 6696–6709

    Not in our library10.1074/jbc.ra118.005889

29. 29.

    Gasset‐Rosa F, Lu S, Yu H, Chen C, Melamed Z, Guo L, Shorter J, Da Cruz S, Cleveland DW (2019 ) Cytoplasmic TDP‐43 de‐mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP‐43, and cell death. Neuron 102: 339–357.e7

    Not in our library10.1016/j.neuron.2019.02.038

30. 30.

    Gowers RJ, Linke M, Barnoud J, Reddy TJE, Melo MN, Seyler SL, Domański J, Dotson DL, Buchoux S, Kenney IM et al (2016 ) MDAnalysis: a python package for the rapid analysis of molecular dynamics simulations. In Proceedings of the 15th Python in Science Conference, pp 98–105. Austin, TX: SciPy 2016

    Not in our library

31. 31.

    Guo Q, Lehmer C, Martínez‐Sánchez A, Rudack T, Beck F, Hartmann H, Pérez‐Berlanga M, Frottin F, Hipp MS, Hartl FU et al (2018 ) In situ structure of neuronal C9orf72 Poly‐GA aggregates reveals proteasome recruitment. Cell 172: 696–705.e12

    Not in our library10.1016/j.cell.2017.12.030

32. 32.

    Haj‐Yahya M, Gopinath P, Rajasekhar K, Mirbaha H, Diamond MI, Lashuel HA (2020 ) Site‐specific hyperphosphorylation inhibits, rather than promotes, tau fibrillization, seeding capacity, and its microtubule binding. Angew Chem Int Ed Engl 59: 4059–4067

    Not in our library10.1002/anie.201913001

33. 33.

    Halfmann R, Lindquist S (2008 ) Screening for amyloid aggregation by semi‐denaturing detergent‐agarose gel electrophoresis. J Vis Exp

    Not in our library10.3791/838

34. 34.

    Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M et al (2008 ) Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64: 60–70

    Not in our library10.1002/ana.21425

35. 35.

    Hofweber M, Dormann D (2019 ) Friend or foe‐Post‐translational modifications as regulators of phase separation and RNP granule dynamics. J Biol Chem 294: 7137–7150

    Not in our library10.1074/jbc.tm118.001189

36. 36.

    Hutten S, Dormann D (2020 ) A quantitative assay to measure stress granule association of proteins and peptides in semi‐permeabilized human cells. Bio‐protocol 10: e3846

    Not in our library10.21769/bioprotoc.3846

37. 37.

    Hutten S, Usluer S, Bourgeois B, Simonetti F, Odeh HM, Fare CM, Czuppa M, Hruska‐Plochan M, Hofweber M, Polymenidou M et al (2020 ) Nuclear import receptors directly bind to arginine‐rich dipeptide repeat proteins and suppress their pathological interactions. Cell Rep 33: 108538

    Not in our library10.1016/j.celrep.2020.108538

38. 38.

    Inukai Y, Nonaka T, Arai T, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle FE, Akiyama H, Hisanaga S‐I et al (2008 ) Abnormal phosphorylation of Ser409/410 of TDP‐43 in FTLD‐U and ALS. FEBS Lett 582: 2899–2904

    Not in our library10.1016/j.febslet.2008.07.027

39. 39.

    Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF et al (2014 ) TDP‐43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol 127: 811–824

    Not in our library10.1007/s00401-014-1269-z

40. 40.

    Kametani F, Nonaka T, Suzuki T, Arai T, Dohmae N, Akiyama H, Hasegawa M (2009 ) Identification of casein kinase‐1 phosphorylation sites on TDP‐43. Biochem Biophys Res Commun 382: 405–409

    Not in our library10.1016/j.bbrc.2009.03.038

41. 41.
    Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains · 2016

    No notice
42. 42.

    Lancaster AK, Nutter‐Upham A, Lindquist S, King OD (2014 ) PLAAC: a web and command‐line application to identify proteins with prion‐like amino acid composition. Bioinformatics 30: 2501–2502

    Not in our library10.1093/bioinformatics/btu310

43. 43.

    Larsen AH, Wang Y, Bottaro S, Grudinin S, Arleth L, Lindorff‐Larsen K (2020 ) Combining molecular dynamics simulations with small‐angle X‐ray and neutron scattering data to study multi‐domain proteins in solution. PLoS Comput Biol 16: e1007870

    Not in our library10.1371/journal.pcbi.1007870

44. 44.

    Laurents DV, Stuani C, Pantoja‐Uceda D, Buratti E, Mompean M (2021 ) Aromatic and aliphatic residues of the disordered region of TDP‐43 are on a fast track for self‐assembly. Biochem Biophys Res Commun 578: 110–114

    Not in our library10.1016/j.bbrc.2021.09.040

45. 45.

    Li HR, Chiang WC, Chou PC, Wang WJ, Huang JR (2018 ) TAR DNA‐binding protein 43 (TDP‐43) liquid‐liquid phase separation is mediated by just a few aromatic residues. J Biol Chem 293: 6090–6098

    Not in our library10.1074/jbc.ac117.001037

46. 46.
    Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. · 2011

    Not checked
47. 47.
    Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43 · 2021

    No notice
48. 48.

    Liachko NF, McMillan PJ, Guthrie CR, Bird TD, Leverenz JB, Kraemer BC (2013 ) CDC7 inhibition blocks pathological TDP‐43 phosphorylation and neurodegeneration. Ann Neurol 74: 39–52

    Not in our library10.1002/ana.23870

49. 49.
    The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43 · 2014

    No notice
50. 50.

    Ling SC, Polymenidou M, Cleveland DW (2013 ) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79: 416–438

    Not in our library10.1016/j.neuron.2013.07.033

51. 51.

    Mackenzie IR, Rademakers R, Neumann M (2010 ) TDP‐43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9: 995–1007

    Not in our library10.1016/s1474-4422(10)70195-2

52. 52.

    Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH (2007 ) The MARTINI force field: coarse grained model for biomolecular simulations. J Phys Chem B 111: 7812–7824

    Not in our library10.1021/jp071097f

53. 53.

    Martin I, Kim J, Lee B, Kang H, Xu J‐C, Jia H, Stankowski J, Kim M‐S, Zhong J, Kumar M et al (2014 ) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157: 472–485

    Not in our library10.1016/j.cell.2014.01.064

54. 54.

    Martin EW, Holehouse AS, Peran I, Farag M, Incicco JJ, Bremer A, Grace CR, Soranno A, Pappu RV, Mittag T (2020 ) Valence and patterning of aromatic residues determine the phase behavior of prion‐like domains. Science 367: 694–699

    Not in our library10.1126/science.aaw8653

55. 55.

    Martin EW, Thomasen FE, Milkovic NM, Cuneo MJ, Grace CR, Nourse A, Lindorff‐Larsen K, Mittag T (2021 ) Interplay of folded domains and the disordered low‐complexity domain in mediating hnRNPA1 phase separation. Nucleic Acids Res 49: 2931–2945

    Not in our library10.1093/nar/gkab063

56. 56.

    Martinez‐Gonzalez L, Rodriguez‐Cueto C, Cabezudo D, Bartolome F, Andres‐Benito P, Ferrer I, Gil C, Martin‐Requero A, Fernandez‐Ruiz J, Martinez A et al (2020 ) Motor neuron preservation and decrease of in vivo TDP‐43 phosphorylation by protein CK‐1delta kinase inhibitor treatment. Sci Rep 10: 4449

    Not in our library10.1038/s41598-020-61265-y

57. 57.
    C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration · 2014

    No notice
58. 58.

    McGibbon RT, Beauchamp KA, Harrigan MP, Klein C, Swails JM, Hernandez CX, Schwantes CR, Wang LP, Lane TJ, Pande VS (2015 ) MDTraj: a modern open library for the analysis of molecular dynamics trajectories. Biophys J 109: 1528–1532

    Not in our library10.1016/j.bpj.2015.08.015

59. 59.

    Michaud‐Agrawal N, Denning EJ, Woolf TB, Beckstein O (2011 ) MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J Comput Chem 32: 2319–2327

    Not in our library10.1002/jcc.21787

60. 60.

    Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP (2015 ) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163: 123–133

    Not in our library10.1016/j.cell.2015.09.015

61. 61.

    Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, Marrink SJ (2008 ) The MARTINI coarse‐grained force field: extension to proteins. J Chem Theory Comput 4: 819–834

    Not in our library10.1021/ct700324x

62. 62.

    Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, Mucke L (2015 ) Tau post‐translational modifications in wild‐type and human amyloid precursor protein transgenic mice. Nat Neurosci 18: 1183–1189

    Not in our library10.1038/nn.4067

63. 63.

    Nedelsky NB, Taylor JP (2019 ) Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease. Nat Rev Neurol 15: 272–286

    Not in our library10.1038/s41582-019-0157-5

64. 64.

    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006 ) Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130–133

    Not in our library10.1126/science.1134108

65. 65.

    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ et al (2009 ) Phosphorylation of S409/410 of TDP‐43 is a consistent feature in all sporadic and familial forms of TDP‐43 proteinopathies. Acta Neuropathol 117: 137–149

    Not in our library10.1007/s00401-008-0477-9

66. 66.

    Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H et al (2016 ) Phosphorylation of TAR DNA‐binding protein of 43 kDa (TDP‐43) by truncated casein kinase 1delta triggers mislocalization and accumulation of TDP‐43. J Biol Chem 291: 5473–5483

    Not in our library10.1074/jbc.m115.695379

67. 67.

    Parrinello M, Rahman A (1981 ) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52: 7182–7190

    Not in our library

68. 68.

    Patel A, Lee H, Jawerth L, Maharana S, Jahnel M, Hein M, Stoynov S, Mahamid J, Saha S, Franzmann T et al (2015 ) A liquid‐to‐solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162: 1066–1077

    Not in our library10.1016/j.cell.2015.07.047

69. 69.

    Perdikari TM, Jovic N, Dignon GL, Kim YC, Fawzi NL, Mittal J (2021 ) A predictive coarse‐grained model for position‐specific effects of post‐translational modifications. Biophys J 120: 1187–1197

    Not in our library10.1016/j.bpj.2021.01.034

70. 70.

    Piana S, Donchev AG, Robustelli P, Shaw DE (2015 ) Water dispersion interactions strongly influence simulated structural properties of disordered protein states. J Phys Chem B 119: 5113–5123

    Not in our library10.1021/jp508971m

71. 71.

    Pietrek LM, Stelzl LS, Hummer G (2020 ) Hierarchical ensembles of intrinsically disordered proteins at atomic resolution in molecular dynamics simulations. J Chem Theory Comput 16: 725–737

    Not in our library10.1021/acs.jctc.9b00809

72. 72.

    Ratti A, Buratti E (2016 ) Physiological functions and pathobiology of TDP‐43 and FUS/TLS proteins. J Neurochem 138(Suppl 1): 95–111

    Not in our library10.1111/jnc.13625

73. 73.

    Regy RM, Dignon GL, Zheng W, Kim YC, Mittal J (2020 ) Sequence dependent phase separation of protein‐polynucleotide mixtures elucidated using molecular simulations. Nucleic Acids Res 48: 12593–12603

    Not in our library10.1093/nar/gkaa1099

74. 74.

    Robustelli P, Piana S, Shaw DE (2018 ) Developing a molecular dynamics force field for both folded and disordered protein states. Proc Natl Acad Sci USA 115: E4758–E4766

    Not in our library10.1073/pnas.1800690115

75. 75.

    Salado IG, Redondo M, Bello ML, Perez C, Liachko NF, Kraemer BC, Miguel L, Lecourtois M, Gil C, Martinez A et al (2014 ) Protein kinase CK‐1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem 57: 2755–2772

    Not in our library10.1021/jm500065f

76. 76.
    Phase separation-deficient TDP43 remains functional in splicing · 2019

    No notice
77. 77.

    Serber Z, Ferrell Jr JE (2007 ) Tuning bulk electrostatics to regulate protein function. Cell 128: 441–444

    Not in our library10.1016/j.cell.2007.01.018

78. 78.

    Strickfaden SC, Winters MJ, Ben‐Ari G, Lamson RE, Tyers M, Pryciak PM (2007 ) A mechanism for cell‐cycle regulation of MAP kinase signaling in a yeast differentiation pathway. Cell 128: 519–531

    Not in our library10.1016/j.cell.2006.12.032

79. 79.

    Taylor LM, McMillan PJ, Liachko NF, Strovas TJ, Ghetti B, Bird TD, Keene CD, Kraemer BC (2018 ) Pathological phosphorylation of tau and TDP‐43 by TTBK1 and TTBK2 drives neurodegeneration. Mol Neurodegener 13: 7

    Not in our library10.1186/s13024-018-0237-9

80. 80.

    Tesei G, Schulze TK, Crehuet R, Lindorff‐Larsen K (2021 ) Accurate model of liquid‐liquid phase behaviour of intrinsically‐disordered proteins from optimization of single‐chain properties. bioRxiv [PREPRINT]

    Not in our library10.1101/2021.06.23.449550

81. 81.

    Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, König J, Hortobágyi T, Nishimura AL, Župunski V et al (2011 ) Characterizing the RNA targets and position‐dependent splicing regulation by TDP‐43. Nat Neurosci 14: 452–458

    Not in our library10.1038/nn.2778

82. 82.

    Tziortzouda P, Van Den Bosch L, Hirth F (2021 ) Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat Rev Neurosci 22: 197–208

    Not in our library10.1038/s41583-021-00431-1

83. 83.
    A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing · 2018

    No notice
84. 84.

    Wang C, Duan Y, Duan G, Wang Q, Zhang K, Deng X, Qian B, Gu J, Ma Z, Zhang S et al (2020 ) Stress induces dynamic, cytotoxicity‐antagonizing TDP‐43 nuclear bodies via paraspeckle LncRNA NEAT1‐mediated liquid‐liquid phase separation. Mol Cell 79: 443–458.e7

    Not in our library10.1016/j.molcel.2020.06.019

85. 85.

    Yaffe MB, Rittinger K, Volinia S, Caron PR, Aitken A, Leffers H, Gamblin SJ, Smerdon SJ, Cantley LC (1997 ) The structural basis for 14‐3‐3:phosphopeptide binding specificity. Cell 91: 961–971

    Not in our library10.1016/s0092-8674(00)80487-0

86. 86.
    Chronic optogenetic induction of stress granules is cytotoxic and reveals the evolution of ALS-FTD pathology · 2019

    No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.