Pathogenesis of ALS
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Pathogenesis of ALS

ALS (Amyotrophic Lateral Sclerosis), also known as Lou Gehrig’s disease, is a devastating neurodegenerative disorder, which is characterized by the selective degeneration of upper and lower motor neurons, the large nerve cells connecting the brain to the spinal cord and from the spinal cord to muscles, which control muscle movement. The loss of motor neurons leads to progressive atrophy of skeletal muscles. ALS is a relentless disease that manifests as progressive decline in muscular function resulting in eventual paralysis, speech deficits and, ultimately, death due to respiratory failure in the majority of ALS patients within 2 to 5 years of clinical onset. In spite of its notoriety, the mechanisms underlying ALS remain obscure and therapies with long-term benefit are lacking. About 90% of ALS cases are Sporadic, and the remaining 10% are inherited in a dominant manner (Familial ALS). The Sporadic and Familial forms of ALS are phenotypically indistinguishable suggesting a convergence of common pathogenic mechanisms in this disease. Mutations in the gene encoding the enzyme SOD1 (Cu/Zn Superoxide Dismutase-1)/ALS1 is believed to be the major cause of Familial ALS. Mutations in ALS2 (Alsin, a Guanine nucleotide Exchange Factor), VAPB (Vesicle Associated membrane Protein-B) and Ang (Angiogenin) also account for a small number of cases. SOD1 is a highly conserved enzyme that is the primary cytoplasmic scavenger of superoxide radical (O2-). Each subunit forms a Greek key Beta-barrel structure that binds one zinc and one copper ion; the zinc contributes to the structural stability of the active site, and the copper is involved in the redox dismutation of the toxic superoxide free radical. Its normal function is to catalyze the conversion of superoxide anions to hydrogen peroxide. Increased toxic misfolding of mutant SOD is believed to be the cause for FALS, analogous to other protein misfolding diseases (Ref.1, 2 & 3 ).

Multiple genetic and environmental factors are implicated in ALS pathogenesis. Many theories of ALS pathogenesis have been proposed, including Oxidative stress, Excitotoxicity, Mitochondrial Dysfunction, Defective Axonal transport and Abnormal Protein Aggregation. The weight of evidence at present favours mitochondrial dysfunction acting with excitotoxicity to cause abnormal protein precipitation as key steps towards the final common path of neurodegeneration via an Apoptotic mechanism. The aetiology is likely to be multifactoral, involving interplay of several mechanisms to initiate disease and propagate the spread of motor neuron cell death. Motor neuron damage as a result of Oxidative stress is a key hypothesis in ALS. SOD1 has the capacity to catalyze the production of ROS (Reactive Oxygen Species) such as Superoxide anions, Peroxynitrite and Hydroxyl radicals. Oxidative stress might also link with other proposed disease mechanisms such as Excitotoxicity and Axonal transport defects. Excitotoxicity leads to increased intracellular Calcium, which in turn leads to increased Nitric Oxide formation. Peroxynitrite, generated by the reaction of Superoxide anions and Nitric oxide, can subsequently lead to Oxidative damage. Nitration may target neurofilament proteins, disrupting their phosphorylation and affecting axonal transport (Ref. 4 & 5).

Glutamate excitotoxicity is another mechanism implicated in ALS pathogenesis, via mechanisms that includes disruption of intracellular calcium homeostasis and free radical production. Glutamate is released from presynaptic terminals, is Ca2+- dependant and activates specific receptors (AMPAR (Amino-3-Hydroxy 5-Methyl-Isoxazole-Propionic Receptor), NMDAR (NMethyl D-Aspartate Receptor) and GluRs (Glutamate Receptors)) on postsynaptic neurons by diffusing across the synaptic cleft. The action of Glutamate in the cleft is terminated by its rapid reuptake via Glutamate transporter proteins. EAAT1 (Excitatory Amino Acid Transporter-1) and EAAT2 (Excitatory Amino Acid Transporter-2) are expressed on Glial cells specially Astrocytes EAAT3 (Excitatory Amino Acid Transporter-3) is mainly on presynaptic motor neurons. EAAT2 is responsible for most Glutamate reuptake in the human brain. Under normal physiological conditions postsynaptic activation of Glutamate Receptors results in a small rise in intracellular Calcium that can be buffered in the cell. When excess Glutamate is present, there is a greater elevation in intracellular Calcium post synaptically. This triggers mitochondrial production of ROS, which then inhibit glial EAAT2 function. EAAT2 is also inhibited by Caspase3Caspase3  activation and impairment in expression and activity of EAAT2 are two distinct molecular mechanisms occurring in human ALS. Excitotoxicity caused by down-regulation of EAAT2 is thought to be a contributing factor to motor neuron death in ALS. Caspase3 cleaves EAAT2 at a unique site located in the cytosolic C-terminal domain of the transporter thus linking excitotoxicity and activation of Caspase3  as converging mechanisms in the pathogenesis of ALS. Caspase3  cleavage of EAAT2 leads to a drastic and selective inhibition of this transporter. This leads to further increases in Glutamate concentrations in the synapse and further rises in postsynaptic Calcium levels and thus excitotoxic degeneration of motor neurons. The oxidative stress evident in ALS might also promote increased excitotoxicity, as Glutamate transporters are particularly susceptible to disruption by oxidants (Ref.1, 6 & 7). The most promising hypothesis is that the toxicity of mutant SOD1 results from the propensity of misfolded protein mutants to aggregate into cytoplasmic inclusion bodies. Aggregation of SOD1 into high molecular weight, IPCs (Insoluble Protein Complexes) is an early event in the pathogenic mechanism.  Abnormal protein aggregates, including Bunina bodies, Ubiquitinated inclusions and neurofilament rich hyaline inclusions are pathological hallmarks of ALS. In addition, an abundance of intracellular aggregates could provoke neurodegeneration by overwhelming the capacity of the protein folding chaperones such as the CCS (Copper Chaperone for SOD1) and/or of Ubiquitin Proteosome pathway to degrade important cellular regulatory factors. Neurofilament proteins (neuron-specific intermediate filaments) are the most abundant structural protein in mature motor neurons, and aggregates of neurofilament proteins in the cell body and proximal axons of motor neurons are commonly seen in ALS. The accumulated neurofilament protein might provide a buffer for other deleterious processes such as increases in intracellular Calcium from excitotoxicity or aberrant protein modification caused by oxidative stress (Ref. 8 & 9).

Mitochondria also play a critical role in the pathogenesis of ALS and are a target for the mutant SOD1 protein. Mutant SOD1 has been localized in the mitochondria binding Bcl2 (B-Cell CLL/Lymphoma-2), the cells primary anti-apoptotic protein. The toxicity of mutant SOD1 may be mediated by damage to mitochondria in motor neurons. Mitochondrial pathology is also present in central nervous system tissue from human ALS cases. Oxidative damage to mitochondrial DNA leading to the accumulation of mitochondrial DNA mutations as well as other mitochondrial damages could be important mechanisms contributing to the selective loss of motor neurons in ALS. Mitochondria dysfunction or damaged mitochondria can produce excess superoxide ion, release CytoC  (Cytochrome-C) into the cytoplasm which activates Caspase3, and affect Ca2+ homeostasis (Ref. 10 & 11). The SOD1 shows axonal transport defects as one of the earliest pathological features of ALS in mouse. Axonal transport, both retrograde and anterograde is especially important in motor neurons because of their large size. The Dynein-Dynactin complex is involved in fast retrograde transport. Mutations in the p150 subunit of Dynactin have been reported in a family with an unusual lower motor neuron disorder that begins with vocal cord paralysis. The Kinesin proteins are important components of anterograde axonal transport. Mutations in the genes encoding Kinesin proteins have been found in human cases of hereditary Spastic Paraplegia and in forms of hereditary motor and sensory neuropathy but have not yet been described in any ALS cases. Recent research has highlighted the potential involvement of Hypoxia-regulated genes in ALS pathogenesis. Hypoxia-induced VEGF (Vascular Endothelial Growth Factor) is found to influence motor neurons via direct neurotrophic effects and via its action to maintain blood flow to highly metabolically active motor. Angiogenin is another hypoxia-induced Angiogenic factor with similar functions to VEGF. Very recent studies have revealed that mutations in this gene are risk factors in SALS and are causative in some FALS cases (Ref.12 & 13).

The mechanism of neuronal death in human ALS occurs through programmed cell death, i.e., apoptosis. There is also compelling evidence that motor neuron death involves apoptosis in disease caused by SOD1 mutations. Moreover, hallmarks of apoptotic death, i.e., DNA fragmentation,Caspase1 and Caspase9 activation, increase in the pro-apoptotic BAX (Bcl2 Associated-X Protein) and BAD (Bcl2-Antagonist of Cell Death) proteins and altered expression of Bcl2  members are also characteristics of ALS. There is evidence that mutant SOD1 can activate p53, a nuclear phosphoprotein protein that may play a causative role in apoptosis (Ref.14 & 15). Presently, ALS is an incurable disease for which there is no effective treatment.  Between diagnosis and death, patients experience progressive muscle weakness, increasing functional disability including, frequently, loss of the ability to speak, inability to breath without mechanical assistance, and, eventually, complete motor paralysis. The physical, emotional, social, and economic burdens of ALS are enormous.  The disease does not necessarily debilitate the patients mental functioning in the same manner as Alzheimers disease or other neurological conditions, however; even those suffering advanced stages of the disease may retain the same memories, personality, and intelligence they had before its onset. Potential therapies for ALS are being investigated in animal models. Some of this work involves experimental treatments with normal SOD1 and other antioxidants. In addition, neurotrophic factors are being studied for their potential to protect motor neurons from pathological degeneration. It is now believed that these and other basic research studies will eventually lead to treatments for ALS (Ref.1, 2 & 16).