Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

1Neurodegenerative diseases, including Alzheimer (AD), Parkinson (PD), Huntington (HD), and Lou Gehrig or amyotrophic lateral sclerosis (ALS), are characterized by inexorable degeneration of specific neural clusters. This class of diseases poses a serious clinical challenge because once the neurodegeneration begins, it can only be slowed down but not fully halted. Typically, the progression of neurodegeneration starts in the subcortical regions and spreads to cortical regions as the disease progresses. The primary neuronal loss varies with the disease such as striatal regions in PD, striatal and cortical regions in HD, hippocampal and cortical regions in AD, and spinal motor neurons and cortical regions in ALS.

2Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, resulting in neuronal death. In these diseases, there are specific neuronal clusters that are primarily vulnerable, which become the original site from which the pathology spreads. These vulnerable neurons have complex morphological features such as long-range neuronal projections and extensive synaptic connections, which makes them selectively vulnerable due to their higher metabolic demands to maintain their structural complexity.

3We hypothesize that energy deficiency occurs at different neural hierarchies, such as subcellular, cellular, and systems levels, may be a root cause of neuronal loss. We propose that the pathological markers of neurodegenerative diseases, such as mitochondrial dysfunctions, protein mishandling, and oxidative stress, are a direct consequence of metabolic abnormalities. Contrarily, energy deficiency can also be triggered by oxidative stress, glutamate toxicity, and excessive calcium load. We also looked into whether protein aggregation is a cause or a symptom of energy deficiency. There may exist a bidirectional relationship between genetic dysfunctions and metabolic abnormalities. However, most cases of neurodegenerative disorders seem to be sporadic, and usually, a definite genetic cause might not be established. The known pathologies of neurodegenerative diseases are listed in Table 1. Viewing these disorders as a result of metabolic abnormalities can open up new avenues of therapeutic research to protect the neuronal population and improve outcomes for patients.

4Current clinical treatments aim at managing clinical symptoms rather than curing the underlying pathological cause. Several US Food and Drug Administration (FDA)–approved treatments available for different neurodegenerative diseases are listed in Table 2. However, these drugs exhibit side effects, such as gait disturbance, rigidity, tremor, hives, headache, drowsiness, nausea, and so on. This shows that, although current medications can reduce the symptoms, there are no permanent solutions to rescue the surviving neuronal population. The leading cause of the selective vulnerability is still unclear. To determine potential drug targets and develop novel therapeutic strategy, it is essential to identify the underlying cause of the disease. In this review, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and the role of metabolic stress related to various pathological events. Because of structural complexity, the vulnerable neurons have higher energy demand, which they try to meet through oxidative phosphorylation. The increased production of adenosine triphosphate (ATP) and depletion of antioxidants induce reactive oxygen species (ROS) response that leads to oxidative stress, which in turn influences the function of mitochondria. Furthermore, aberrant glutamate signaling leads to excessive calcium load that additionally induces metabolic and endoplasmic reticulum (ER) stress. Any slight perturbation in the energy metabolism affects these neurons tremendously. From this literature background, we propose a plausible mechanism for selective neurodegeneration, which argues that an imbalance between energy supply and demand impacts these specific neurons at a higher rate compared to other neuronal populations.

5In various neurodegenerative disorders, a specific population of neurons is selectively vulnerable because of their structural and functional complexity (Figure 1). In case of PD, there is a significant loss of dopaminergic neurons, specifically in the substantia nigra pars compacta (SNc) region (Figure 1). However, dopaminergic neurons, which are abundantly present in other regions, such as ventral tegmental area (VTA) and olfactory bulb, are affected to much lesser extent. What is the distinctive vulnerability of SNc neurons compared to neurons in the VTA? The possible reason could be that SNc neurons possess complex arborization and extensive synaptic connections, which result in a higher basal metabolic rate and increased oxidative stress compared to other closely related dopaminergic neurons such as those of VTA and olfactory bulb.

6In AD, hippocampal neurons located in the cornu ammonis 1 (CA1) field are selectively vulnerable (;; Figure 1). In AD patients, the volume of the neuronal population in the CA1 region is significantly smaller than in other regions (CA2, CA3) of the hippocampus. Electrophysiology studies showed that the overall firing rate of the CA1 population is higher than that of the CA3 population, which makes CA1 neurons a more energy-craving neuronal population compared to other hippocampal fields. Thus, under ischemic stress, a higher number of neurons in the CA1 region were susceptible when compared to the CA3 region in the rat brain. Anatomical studies showed differences between the vascular architecture in CA1 and CA3 regions; CA1 region contains a large ventral artery, whereas a higher number of capillaries were found in the vicinity of CA3 neurons. These vascular features can be linked to the higher energy requirements of CA1 neurons compared to CA3 neurons.

7In ALS, Fast-Fatigable (FF) motor neurons, which are a subset of α motor neurons, are specifically vulnerable compared to other motor neurons (Figure 1;;; ). As this subgroup of motor neurons involved in intense movements such as jumping and running, they require an enormous amount of energy for their functioning, which makes them vulnerable under metabolic abnormalities. Moreover, because of their enormous axonal arborization and large axonal diameter when compared to other closely related slow motor neurons, FF motor neurons require a greater amount of energy to maintain and propagate information across their complex axonal structures. Electrophysiology studies show that the overall firing rate of FF motor neurons was higher when compared to slow motor neurons because of shorter after-hyperpolarization latency following an action potential, which makes FF motor neurons a more energy-craving neuronal population compared to others. As a result of higher energy requirements of FF motor neurons, they are prone to higher ER stress compared to slow motor neurons. Thus, it indicates that FF motor neurons tend to be more vulnerable when compared to slower motor neurons in similar stress conditions.

8In HD, enkephalin-positive medium spiny neurons (MSNs) of striatum are selectively vulnerable (;;; Figure 1). The MSNs (GABAergic/enkephalin) projecting to globus pallidus externa (GPe) through the indirect pathway tend to die earlier in disease pathogenesis. The striatal MSNs and cortical pyramidal neurons (projection neurons) are more vulnerable to degeneration due to their peculiar long axonal arborization that projects to distant regions in the brain. Contrarily, the striatal and cortical interneurons are less vulnerable due to their extensive dendritic network that projects locally when compared to projection neurons, which have long-range projections. To maintain this complex axonal arborization, projection neurons require enormous energy, much more than a typical neuron. In HD, enkephalin levels are reduced during pathogenesis, but overexpressing pre-enkephalin alleviates HD symptoms. The polyglutamine-huntingtin (polyQ-Htt)–induced toxicity does not occur selectively in any specific neuronal population, but cell-specific features might differentially render specific neuronal populations increasingly vulnerable to polyQ-Htt–induced toxicity. However, it is still not clear why enkephalin-positive MSNs are more vulnerable in HD compared to substance P positive MSNs.

9Several studies reported that mitochondrial-derived energy failure inhibits synaptic vesicle recycling in presynaptic boutons, which leads to neurodegeneration in hippocampus and striatum. The accumulation of α-synuclein in mitochondria was reported in substantia nigra and striatum in PD patients, which can hinder mitochondrial functions. It has been reported that the cerebral metabolic rate of glucose was reduced by ∼25% in case of AD patients. It was reported that glucose consumption was reduced in the brain, especially in the basal ganglia in HD patients and presymptomatic mutation carriers also. The energy homeostasis in ALS patients was observed to be disrupted, where energy uptake was decreased, and energy consumption was increased, which results in reduced fat deposits in ALS patients. Thus, these studies support the idea of energy deficiency as a cause of neurodegeneration.

10In summary, all the aforementioned neurodegenerative diseases indicate that vulnerable neurons have high energy demands due to their anatomical complexity and rich synaptic connectivity. These regions act as energy-craving hubs, and deterioration in the energy supply could lead to neurodegeneration.

11The neurons susceptible to degeneration need higher energy to maintain their structural and functional integrity. Therefore, any disruption in energy metabolism can lead to enormous energy demand that eventually results in cellular stress. Because mitochondria are vital for oxidative energy metabolism, mitochondrial dysfunction is a major contributor to metabolic stress. Increased production of ATP results in higher ROS production. Inadequate antioxidants, scavenging enzymes, and functional abnormalities in the mitochondria can cause oxidative stress. This oxidative stress affects mitochondrial DNA (mtDNA) and leads to an aberration in mitochondrial quality control and electron transport chain enzymes, which results in metabolic deficiency. Furthermore, this may also result in broken cristae and other structural abnormalities in mitochondria. Along with morphological abnormalities in mitochondria, increased calcium influx and overproduction of ROS may accelerate the formation of inner mitochondrial transition pore (MTP), which leads to apoptosis.

12SNc dopamine (DA) neurons exhibit elevated rates of oxidative phosphorylation, showing a threefold increase in ATP production and ROS generation in SNc compared to VTA neurons. A higher density of mitochondria in SNc axonal arbor compared to VTA indicates a higher energy requirement for the functioning of SNc neurons.

13Higher levels of superoxide and ROS were observed in the CA1 region compared to the CA3 region from in vitro studies. This result shows that there is an aberrant oxidative phosphorylation mechanism in CA1 neurons, which results in augmented ROS production. In vivo studies demonstrate that ROS and calcium-induced stress in the CA1 region activates MTPs at higher rate, leading to calcium-induced mitochondrial swelling compared to the CA3 region. These studies illustrate that these two neuronal populations respond differently to similar stress conditions. In rodent studies, severe mitochondrial damages were observed in the CA1 region when compared to the CA3 region in post-ischemic conditions. Thus, neurons in the CA1 region are more susceptible to mitochondrial damage and oxidative stress when compared to the CA3 region. Human gene expression studies reveal that genes involved in energy metabolism were downregulated in AD. Also, reduced activity of glycolytic and oxidative phosphorylation enzymes was observed in AD patient samples. Thus, these studies suggest that CA1 neurons are more susceptible to oxidative stress because of their enormous energy requirements.

14In order to study the role of mitochondria in ALS pathogenesis, mitochondrial enzymatic activity was recorded from various neuronal tissues (brain and spinal cord) of mice expressing human superoxide dismutase 1 (SOD1) mutant (hSOD1-G93A). They found that cytochrome oxidase (complex IV) and ROS-scavenging activity were significantly lower in motor neurons, which resulted in increased mtDNA deletions. A large number of mtDNA deletions were observed in ALS patients, which might be due to reduced ROS-scavenging activity. The reduced axonal mitochondria were associated with aberrant axonal transport as a result of aggregated toxic SOD1 interfering with the functioning of dynein motor proteins, which are involved in retrograde transport (i.e., it transports the damaged mitochondria or misfolded protein from the axonal terminal to the soma for degradation). Besides, SOD1 mutant mice showed that increased ROS response impairs energy production as well as inhibits the cargo activity as a consequence of higher energy demand. This might be due to increased level of ROS, which in turn impairs both mitochondrial functionality and protein degradation, thereby inhibiting the cargo activity.

15Functional assay studies have demonstrated that rat striatal mitochondria are more selective in forming MTPs in response to ROS and calcium-induced stress than the mitochondria in the cortical neurons. Furthermore, HD knock-in studies illustrate that ROS and reactive nitrogen species (RNS) were predominately observed in striatal cells and impact the electron transport chain. A greater mitochondrial mass was found to be present in the striatum, and significant mtDNA deletions were observed in HD transgenic mice when compared to other brain regions as a result of reduced ROS-scavenging activity. The gene expression studies of HD patients showed increased levels of antioxidants and severe defects in the activity of the respiratory chain complexes (II, III, and IV) in striatum as a consequence of oxidative stress.

16In summary, the characteristic features among all the above neurodegenerative diseases include increased number of mitochondria in vulnerable neuronal populations, increased ROS responses, aberrant respiratory chain enzymes, and higher ATP production. In general, these neurons require more substantial amount of energy to perform the electrical-spiking activity, even small perturbations in energy production mechanisms and mitochondrial functioning significantly affect these neuronal populations compared to others. Calcium-induced stress and increased ROS response impair mitochondrial functionality by disrupting mtDNA, which in turn affects mitochondrial morphology and oxidative energy metabolism. All these events form MTPs, thereby leading to apoptosis. Transgenic mice studies showed that overexpression of peroxisome proliferator activator receptor and γ-coactivator 1α exhibits increased mitochondrial biogenesis, which improves neuronal activity and electron transport energy metabolism. Restoration of mitochondrial function may thus improve neuronal survivability by reducing cellular stress.

17Glutamate is an essential excitatory neurotransmitter that can lead to toxicity when present at high concentrations. Glutamate toxicity may manifest at different levels in the brain (such as subcellular, cellular, or systems level). At subcellular level, differential expression of calcium-binding (CBP) and calcium-sensing proteins can lead to inadequate calcium-buffering capacity, resulting in oversensitivity of neurons to glutamate released extracellularly. At cellular level, the glutamate concentration is affected by differential expression of glutamatergic and neuropeptide receptors. Additionally, extensive arboreal structures can tend to hyperexcitation of glutamate receptors even at the physiological levels of glutamate concentration. Finally, at systems level, overexcitation from pathogenic nuclei can lead to calcium accumulation in ER and mitochondria, which in turn results in neurodegeneration. Considering the factors mentioned above, we infer that certain types of cells might be more vulnerable in pathological conditions, as depicted in Figure 2.

18An excess amount of glutamate damages SNc neurons by activating N-methyl-D-aspartate (NMDA) receptors. During the pace-making activity of SNc neurons, magnesium blockage of NMDA receptors becomes ineffective; as a result, a slight increase in glutamate stimulation creates a calcium storm in these neurons. This direct mechanism of toxicity is possible in case of acute neurological disorders such as ischemic/hypoxic damage to the brain, but not in slowly evolving chronic disorders such as PD. However, under energy deficit conditions, even physiological levels of glutamate are toxic as a result of increased intracellular calcium concentration. This leads to oxidative stress through a mechanism known as “indirect excitotoxicity or weak excitotoxicity”. It was reported that glutamatergic excitation of SNc neurons by subthalamic nucleus (STN) neurons under the conditions of bioenergetic deficiency may lead to aggravation of degeneration processes (;;; Figure 2). The excitotoxic loss of SNc neurons might be due to disinhibition of STN (low DA) precipitated by energy deficiency. Apart from regulation by plasma membrane calcium pumps, ER, and mitochondria, intracellular calcium is also regulated by CBPs (calbindin and calmodulin), which are widely expressed in many brain regions. The presence of calbindin in midbrain DA neurons suggests being a marker to distinguish DA neurons with higher susceptibility to neurodegeneration in PD. The gene expression of calbindin was higher in VTA neurons when compared to SNc neurons in rats and humans. Hence, lower levels of calbindin, heterogeneous expression of NMDA receptors, and overexcitation by STN may result in lower intrinsic calcium-buffering capacity of SNc neurons. Thus, inadequate calcium-buffering capacity may contribute to their selective vulnerability.

19In case of CA1 neurons, the gene expression studies of AD-like rats showed differential expression of NMDA receptor subunit (NR1, NR2B) in the CA1 and CA3 regions. NR2B subunit is highly selective for calcium ion transport and is known to play a decisive role in calcium-induced apoptosis. In AD-like rats, it has been shown that NR2B was overexpressed in the CA1 subfield compared to controls. The persistent overactivation of NMDA receptor in the postsynaptic terminal stimulates CA1 neurons, which allows higher calcium influx resulting in excitotoxicity. During prolonged glutamate stimulation, calcium influx was higher in CA1 compared to CA3, and a substantial amount of calcium is sequestered in CA1 mitochondria. Therefore, dysregulation of calcium homeostasis in the CA1 region forms MTPs, which disrupt the mitochondrial structural integrity and, in turn, affect mitochondrial functioning. Furthermore, it has been reported that CA3 neurons innervate glutamatergic projections to CA1 neurons known as Schaffer collaterals. In AD, CA3 neurons are observed to be overactive, which may cause excitotoxic damage to CA1 neurons (; Figure 2). In aging rats, the reduction of calbindin expression was more significant in CA1 neurons compared to CA3 neurons. In AD, the gene expression of neurofilament proteins and CBPs (parvalbumin, calbindin, and calretinin) was lower in CA1 neurons compared to CA3 neurons. Hence, lower levels of CBPs, heterogeneous expression of NMDA receptor subunits, and overexcitation by CA3 may result in lower intrinsic calcium-buffering capacity. Because of their inadequate calcium-buffering capacity, CA1 neurons are more prone to excitotoxic degeneration in AD.

20Excess glutamate in the synapse or extracellular space is transported into neuronal and glial cells via glutamate transporter excitatory amino acid carrier 1 and glutamate transporter 1 (GLT-1), respectively. In healthy monkeys, it has been noted that increased expression of GLT-1 astroglial elements was observed in vulnerable FF motor neurons when compared to slow motor neurons. However, in case of ALS, lower expression of GLT-1 astroglial elements results in excess glutamate in the synaptic cleft, which leads to excitotoxicity in FF motor neurons. In general, FF motor neurons are hyperexcitable, and they receive glutamatergic projections from the pyramidal neurons of motor cortex. Moreover, in case of FF motor neurons, the ratio of excitatory to inhibitory synapses is higher, which makes them more vulnerable to excitotoxicity under metabolic abnormalities due to disrupted calcium homeostasis (; Figure 2). The normal expression of CBPs, such as calmodulin, calbindin, and parvalbumin, is necessary to maintain calcium homeostasis. The expression of CBPs in FF motor neurons was lower when compared to slow motor neurons, which may result in aberrant calcium regulation in FF motor neurons. The abundant glutamate activates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and increased presence of AMPA receptors was observed in spinal motor neurons. Consequently, AMPA receptors allow greater calcium influx into the mitochondria. To regulate calcium levels, mitochondria require a large energy threshold that eventually leads to metabolic stress. It also produces ROS, which is toxic to spinal motor neurons. The studies mentioned above show that aberrant glutamate reuptake, dysfunction of calcium-buffering proteins, and increased glutamatergic drive cause overexcitation of postsynaptic neurons, which allow greater calcium influx, leading to disruption of neuronal metabolic functions.

21Striatal MSNs receive rich glutamatergic and dopaminergic inputs from cortex and SNc, respectively. Any imbalance in neurotransmission might make MSNs more susceptible to glutamate-induced toxicity (Figure 2). In the early stages of HD, there is a loss of D2-type DA receptor (D2) binding in the striatum and increased GABAA receptor binding in GPe, which suggests that medium spiny GABAergic/enkephalin neurons (D2 MSNs) in the indirect pathway are overexcited, leading to excitotoxicity. Any energy imbalance would increase stress on MSN, which can be exacerbated by polyQ-Htt, leading to (weak) excitotoxicity even at physiological concentrations of glutamate. The expression of CBPs (calretinin, parvalbumin, and calbindin) is higher in striatal interneurons compared to the MSNs; these proteins may act as neuroprotective agents against calcium insults. In HD, the expression of calcium-sensing proteins, such as hippocalcin, reduced in MSNs compared to striatal interneurons, thereby increasing the vulnerability of MSNs. The presence of calcium-binding and calcium-sensing proteins makes striatal interneurons less vulnerable than MSNs. The alterations in glutamate receptor trafficking and functionality, glutamate transport, lower intrinsic calcium-buffering capacity, and energy disruptions might together favor toward excitotoxic death of MSNs.

22The vulnerability of specific neuronal populations in neurodegenerative diseases can be an accumulated effect of many factors across several levels of hierarchy from subcellular to systems level. There can be a positive feedback relationship between metabolic deficiency and disruption in some other factor (such as cell death), each reinforcing the other. A key player across multiple levels of hierarchy is calcium, which is essential for many cellular processes in the neuron. However, excess accumulation of calcium can lead to mitochondrial dysfunctions, oxidative stress, and protein mishandling. In summary, the differential expression of glutamate transporters, glutamate receptors, and calcium-buffering proteins results in aberrant glutamate uptake, which leads to the sequential development of pathology as follows: overexcitation of the vulnerable neuronal population, imbalance in the calcium homeostasis, formation of MTP, mitochondrial swelling, and finally apoptosis.

23One common element in all neurodegenerative diseases is the misfolded (or) damaged protein, which gets accumulated in the intracellular region of a neuron as an insoluble protein aggregate. The various stress factors influence protein aggregation, and aggregated proteins affect neuronal functionality, which results in cell death. Proteins undergo aggregation due to oxidative stress, excitotoxicity, and inflammation. Predominantly, these aggregates are degraded by ubiquitin and lysosomal-mediated degradation processes. Increased oxidative stress influences the proteostasis and deteriorates ubiquitin-mediated proteasomal degradation mechanism. These protein degradation processes required higher levels of ATP for their normal functioning. The increased ROS and reduced ATP generation make the intracellular environment hostile enough to form protein aggregates. These aggregates affect vesicle transport and fuse with the mitochondrial membrane, which in turn increases the permeability that leads to mitochondrial swelling and apoptosis.

24In PD, healthy α-synuclein proteins may get misfolded because of mitochondrial dysfunction or oxidative stress or both, which in turn leads to formation of aggregates and Lewy bodies (LBs). In the recent years, it has been claimed that a viral, neurotoxic or prion-like infection could be a cause of PD pathogenesis. There exist evidences supporting the Braak hypothesis of LBs, which suggests that the pathology (misfolded α-synuclein protein) spreads from peripheral regions of the nervous system to the central nervous system through transsynaptic transmission in PD. The presence of LBs in grafted embryonic DA neurons in PD patients also supported this view of causation. To regard PD as a prion-like disease, it should satisfy one of the two rules – nearest neighbor rule or synaptic connectivity rule – but there is no clear evidence for the same, as discrete distribution patterns of LB pathology undermine the nearest neighbor rule within PD patients, and synaptic connectivity rule was not supported by connectomic data. Thus, there is no clear evidence to consider PD as a prion-like disease. However, α-synuclein aggregation might contribute to oxidative stress by inhibiting mitochondrial function. It was reported that mitochondrial-induced oxidative stress causes dysregulation of calcium and DA, which leads to α-synuclein aggregation and lysosomal dysfunction. Thus, oxidative stress might be caused by α-synuclein aggregation due to metabolic deficiency–derived dysfunctions of ROS-scavenging process. Contrarily, α-synuclein aggregation might be caused by oxidative stress due to metabolic deficiency.

25In AD, β-amyloid and tau proteins are the major contributors to protein aggregation. β-Amyloid is involved in synaptic vesicle transport, and tau protein is essential for microtubule structural organization. Due to environmental stress, these proteins tend to disrupt their structure and functionality, which results in formation of protein aggregates. β-Amyloid plaques form aggregates around neurons and mitochondria, which disrupt their functions. These plaques tend to trigger dysfunction of various mitochondrial proteins that, in turn, affect the cell morphology. Further, additional energy is required to disintegrate the aggregation. The age-dependent glucose hypometabolism and oxidative stress lead to ATP decline in neurons. Therefore, metabolic stress caused by energy demand leads to dysregulation of lysosomal, proteasomal-mediated degradation mechanism, resulting in higher propensity of protein aggregation in the neuron.

26It has been reported that familial mutant SOD1 forms a toxic aggregate, which impairs Na-K-ATPase α3 activity by interacting with its nucleotide-binding site, thereby interfering with neural firing activity. Furthermore, Na+/K+ Na-K-ATPase α3 is abundant in spinal motor neurons. Thus, misfolded protein tends to lose its structural features and form an insoluble aggregate, which induces cellular stress and eventually disrupts neuronal function. The defective protein is usually tagged with ubiquitin for proteasomal degradation, which requires ATP. Ubiquitin C-terminal hydrolase L (UCHL1) is essential for the cerebrospinal muscular junction. It was reported that reduced activity of UCHL1 is associated with defective ubiquitination process, which, in turn, results in increased ER stress. Furthermore, lowered neuronal energy metabolism results in dysregulation of ATP-mediated protein degradation.

27In HD, genetic instability of Htt gene translates into mutant protein Htt, which contains disease-causing expansions of glutamines that make them misfold and form aggregates. These aggregates bind to mitochondria resulting in oxidative stress. In striatum, MSNs are less enriched by superoxide free radical scavengers such as SOD1 and SOD2 when compared to cholinergic interneurons. This difference probably makes MSNs more prone to oxidative stress, which contributes to protein aggregation.

28In summary, protein aggregation is a common phenomenon in normal cells. These proteins are broken down by various degradation processes. Under energy deficiency conditions, neurons possess high energy requirements that lead to excess ROS build-up and exacerbate inflammatory response. Depletion of ATP and protein degradation mechanisms may induce the propensity of protein aggregation, which is deleterious to neuronal function.

29Microglia are also referred to as the military of the brain because they are highly mobile, can sense a threat, and fight against it. The increased ROS and tissue injury activate resting microglia by sensing the signals released by damaged neurons. Microglia play dual roles – they can be a friend or a foe to brain tissue. Under normal conditions, they nurture and sustain the neural tissue by providing neurotrophic, neuroprotective, and neurotoxic factors. Under pathological conditions, the overactivated microglia produce higher amount of inflammatory cytokines that can cause neuronal death. Microglia also activate reactive astrocytes by forming glial scars, which protect healthy tissue from inflammatory signals. Growing experimental evidence demonstrates that reactive gliosis blocks regeneration of axons, synaptic formation, and phagocytic activity by releasing neurotoxic substances.

30From animal models of PD, it was observed that the pattern of cell loss was regulated by the level of oxidative stress caused by inflammation. In human subjects, it was suspected that inflammation and microglial activation might contribute to disease progression in late stages. Astrocytes play a modulatory role in microglial activation. Miscommunication between astrocytes and microglia results in neuroinflammation, which eventually leads to neurodegeneration. It has been reported that neuromelanin can induce microglial activation. Substantia nigra pars compacta neurons are more susceptible to neuromelanin-induced inflammation compared to VTA neurons because of their high neuromelanin biosynthesis. It has also been reported that cyclooxygenase-2 (COX-2) gene is overexpressed in SNc neurons, which are classic proinflammatory mediators, and leads to degeneration in PD. From these pieces of evidence, it may be understood that SNc neurons are prone to be more vulnerable to PD pathogenesis compared to other brain regions.

31In AD, reactive gliosis occurs at higher levels in the CA1 region compared to others. Due to metabolic stress, CA1 astrocytes exhibit increased ROS response, decreased mitochondrial fidelity, and reduced activity of glutamate transporters, leading to tremendous stress in CA1 neurons. Several researchers hypothesized that because of metabolic stress, astroglia turns into inflammatory cells, relinquishing their neurosupportive roles. Activated glial cells are also potential sources of ROS and RNS. Overproduction of nitridergic species, such as peroxynitrite and nitric oxide, is said to be dependent on activated glial cells in addition to the mitochondria. Astrocytes interact with endothelial cells and maintain the blood–brain barrier (BBB) permeability. During pathological conditions, astrocytes release cytokines that disrupt BBB permeability. All these events in the brain lead to disturbed homeostasis and drive disease progression.

32Microglia, astrocytes, oligodendrocytes, and Schwann cells play vital roles in disease progression as glial pathology is observed in all cases of familial and sporadic ALS. Microgliosis is found to be an early and typical hallmark of the disease. In ALS, astrogliosis leads to dysfunction in the glutamate transporter system that results in excitotoxic motor neuron cell death. Post-mortem studies of ALS patients revealed reduced numbers of oligodendrocytes, which leads to reduced capacity to release lactate, causing oxidative stress. Such defects lead to glutamate excitotoxicity, glia cell pathology, mitochondrial damage, and defective axonal transport. Because astrocytes are devoid of their calcium-signaling mechanisms in ALS, elevated calcium levels tend to disrupt the mitochondria and induce oxidative stress, which leads to higher tendency of apoptosis mediated by cytochrome c.

33Astrocytes play a vital role in HD when compared to microglia. Studies showed that striatal astrocytes were unable to handle the calcium and glutamate signaling in HD. An increased amount of glutamate in the synaptic cleft may induce glutamate-mediated excitotoxicity. Calcium mishandling leads to an increased calcium influx inside the cell and disrupts the mitochondrial morphology. Mutant Htt in astrocytes and neurons elevate the microglial response, which induces cytotoxicity.

34Hence, glia–neuron interactions can intensify pathogenesis in the brain and interfere with signaling pathways and normal metabolism. Gliodegenerative events in neurodegenerative diseases disrupt the calcium homeostasis and glutamate transport and induce an inflammatory response. These events cause havoc in the brain, which correlates to disease conditions. In summary, mitochondrial bioenergetics and glial pathology can be interlinked in the pathogenesis of neurotoxicity.

35Because the cerebrovascular network is the source of energy substrates of neural tissue, metabolic deficiency in the neural tissue can be traced to disruptions in cerebrovascular function. The BBB, which serves as a gateway between the cerebrovascular systems and the brain, comprises tight junctions of endothelial cells, pericytes, and basal membrane. Blood–brain barrier is essential to preserve the brain against pathogenic invaders. The vascular region supplies the metabolites and neurotrophic factors to energy-demanding neurons directly via the medium of extracellular space and indirectly via the glial cells. Studies on various neurological disorders report that impairment of BBB and the vascular network lead to neuroinflammation, increased endothelial cell permeability, reduced glucose transport, and invasion of toxic substances, which eventually affect neurovascular communication and cerebral blood flow (CBF). Cerebral blood flow is an essential source of blood glucose supply and helps to preserve functional homeostasis of the neuron. Studies have shown reduced regional CBF in AD, PD, HD, and ALS.

36In a classic experiment aimed to study the role of oxidative stress in various hippocampus subfields, oxygen supply to various neuronal subfields was reduced and then measured the blood vessel count in normal and stress-subjected neuronal populations. Because of ischemic stress, the number of blood vessels drastically reduced in CA1 compared to other regions. This demonstrates that there is a regional vascular vulnerability associated with the CA1 region, which in turn depletes the blood supply to the specific subregion. In ALS, studies have shown discrepancies in barrier conditions, especially in the pericyte region, which leads to increased pinocytosis and affects BBB integrity. From the above studies, it was observed that BBB integrity was disturbed in various neurodegenerative disorders. Blood–brain barrier disruption leads to impairment in vascular–glial communication, resulting in energy crisis, and impacts the functioning of energy-craving neurons. Because of increased energy demand, these vulnerable neurons are unable to meet their energy requirements for securing functional homeostasis.

37Insulin is a primary regulating hormone in the human body, which plays a crucial role in glucose and lipid metabolisms. Lower levels of insulin are observed in cerebrospinal fluid in contrast to plasma in AD. Abnormalities in insulin receptors and their sensitivity are observed in PD, ALS, and HD. However, this insulin resistance leads to an increased amount of advanced glycation end products and upregulates neuroinflammatory signals (nuclear factor κB, tumor necrosis factor α, cytokines), causing vascular injury as well as dysregulate nitric oxide production in endothelial cells, which impairs the vasodilatory effects. Age-dependent insulin resistance dysregulates the insulin receptor abundance and glucose transporters in BBB, which depletes glucose supply to the neuron, in turn, leading to glucose hypometabolism. Insulin regulates cholesterol metabolism that is essential for myelination and regulation of amyloid protein degradation enzymes. Impairment of insulin regulation upregulates low-density lipoproteins and downregulates high-density lipoproteins, which results in amyloid aggregation. Insulin resistance results in an imbalance in glucose metabolism (disruption of endothelial barrier integrity) by causing abnormalities in glucose uptake and oxidation, decreasing the synthesis of glycogen, and reducing the ability to suppress lipid metabolism. Aberrant glucose homeostasis causes chronic hyperglycemia, which results in oxidative stress (aberrant mitochondrial function and nitric oxide synthase (NOS) phosphorylation). Increased oxidative stress results in an inflammatory response by activating microglia and reactive astrocytes, which in turn result in cellular damage.

38Aging plays a vital role in determining the progression of neurodegenerative disorders. During aging, SNc, CA1, and striatal neuronal populations tend to diminish. In some cases, studies have shown selective degeneration of synaptic inputs in FF motor neurons, as opposed to cell death. To understand regional vulnerability, researchers measured protein kinase B (also known as AKT) gene expression level. AKT is essential for neuronal survival, growth, and angiogenesis, which is downregulated in AD, PD, and HD. However, reduced amount of AKT shows a significant increase in proapoptotic signals (FOX3a). Furthermore, changes in AKT expression may be a potential pathway to induce apoptosis. Age-related glucose hypometabolism, morphological structures, and insulin resistance affect these neurons drastically and lead to an energy crisis.

39During typical aging, it has been reported that SNc neurons exhibit compensatory changes (hypertrophy), which result in normal motor function despite cell loss. However, in case of PD, this compensatory mechanism is compromised, resulting in impaired motor function. The vulnerability of SNc DA neurons in PD is further amplified by reduced expression of calbindin in aging. There is no clear justification for why aging is a significant risk factor in PD. However, there are several speculations that deteriorating mitochondrial function might be a significant factor that results in hypometabolism.

40During aging, the CA3 region is hyperactivated, whereas the CA1 region showed a reduced firing rate. As we age, overexcitation of excitatory neurons leads to an excessive accumulation of glutamate in the synaptic cleft, which results in glutamate-induced toxicity. In aging, larger numbers of reactive astrocytes (A1) are observed in CA1 and striatal regions that, in turn, induce neuroinflammation and vulnerability in pyramidal neurons and MSNs of CA1 and striatal regions, respectively. Studies have shown age-dependent increase in the β-amyloid, α-synuclein, SOD1, and Htt protein aggregation. Because of the energy crisis, this type of aggregation leads to enormous stress in the specific neuronal classes.

41From the literature review presented in this article, we propose a causative hypothesis for selective neurodegeneration (Figure 3).

42Typically, in any neurodegenerative disease, the surviving selectively vulnerable neuronal population retains complex axonal arbors and large number of synaptic connections that exhibit elevated energy demand for maintaining the structural and functional integrity.

43Neurons mainly depend on oxidative phosphorylation for their elevated energy requirements. Because of increased energy demand, mitochondria tend to produce excess ROS. The depletion of antioxidants alleviates ROS level above a certain threshold, which subsequently affects the mitochondrial morphology by forming MTP and leads to metabolic stress.

44Impaired glutamate transporter function in the glial cell leads to excessive glutamate accumulation in the synaptic cleft that activates postsynaptic AMPA/NMDA receptors. This allows increased calcium influx in postsynaptic neurons, disrupting calcium homeostasis in the mitochondria and ER and producing excessive levels of ROS.

45Because of metabolic stress, the degenerative neurons release inflammatory cytokines, which can be sensed by astrocytes and microglia. However, the reactive astroglia forms a glial scar, which can protect as well as attack the stressed/injured neuronal population. The increased inflammatory response can also lead to excess ROS formation.

46The increased inflammatory and ROS responses may strain the endothelial cells and pericytes in BBB and result in increased permeability of the membrane, which in turn allows toxic invaders inside the brain. These events further enhance inflammatory response, disrupt vascular integrity, and reduce regional CBF in various neurodegenerative diseases.

47The communication loss between glia and vascular systems leads to insulin resistance that additionally induces inflammation and reduces glucose uptake, which leads to glucose hypometabolism. Moreover, the reduced levels of glucose influence the lactate shuttle, which in turn results in diminished oxidative phosphorylation.

48All the above events impose significant metabolic stress on the neural populations that are already selectively vulnerable due to their distinct structural and functional characteristics. Along with this energy crisis, additional cytotoxic factors, such as protein aggregation, genetic risk factors, and calcium load, expand the vulnerability of these neurons at a higher rate compared to others. This shows an imbalance between energy supply and demand, which seriously challenges the survivability of the energy-craving neuron and leads to selective neurodegeneration.

49Neurons that are selectively vulnerable to metabolic deficiency possess complex arboreal structures and functional responsibilities and therefore require an enormous amount of energy for their survival. The increased production of ATP leads to an increase in ROS formation in mitochondria, which indirectly affects the mitochondrial quality control and respiratory chain enzymes (energy metabolizing enzymes), and, in turn, leads to metabolic stress. Furthermore, dysfunction in glutamate receptors and transporters may hyperexcite postsynaptic neurons, which in turn causes calcium accumulation inside the mitochondria and ER that drives neuronal cells to metabolic stress. In addition, damaged/injured neurons send inflammatory signals that lead to activation of microglia and reactive astrocytes. The increased immune response may affect endothelial cells in BBB that impacts vascular integrity and cerebral blood pressure, which in turn leads to reduced CBF and increased insulin resistance. This may contribute toward glucose hypometabolism, resulting in lesser lactate uptake and affecting oxidative phosphorylation in the vulnerable neuron. Along with this tremendous metabolic stress, an additional toxic substance, protein aggregation, and glutamate excitotoxicity may affect these energy-craving neurons at a higher rate compared to other neurons. Based on the above observations, we propose an integrative theory for neurodegeneration, which suggests that these neuronal populations crave for energy, and any deterioration in the energy supply may perturb these neurons immensely. Restoration of metabolic function may save these vulnerable neurons from going down the path of neurodegeneration.

50VM and SD equally contributed to writing the main text and gathering all references. VC and MG contributed to editing the manuscript drafts, providing insight into structure, and material that should be included.

51The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.