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Pathophysiology of Amyotrophic Lateral Sclerosis

Although the exact molecular pathways of motor neurons death in ALS are still unknown, the main mechanisms such as, the toxic effects of SOD1 mutations, abnormal protein aggregation, disorganization of intermediate filaments, and glutamate-mediated excitotoxicity and various other abnormalities in regulation intracellular calcium in a process that can involve mitochondrial abnormalities and apoptosis.

1. SOD1-Induced Toxicity.

Sporadic and familial ALS are clinically and pathologically similar, so they are likely to have the same pathogenesis. Although only 2% of patients with ALS have a mutation in SOD1, the discovery of this mutation is essential in ALS research. SOD1 is an enzyme that requires copper, catalyzing the conversion of toxic superoxide radicals to hydrogen peroxide and oxygen. Copper atoms mediate the catalysis process. SOD1 also has peroxidation abilities, including peroxidation, radical hydroxyl formation, and tyrosine nitration. SOD1 mutation that interferes with antioxidant function causes toxic accumulation of superoxide. The hypothesis that decreased function as a cause of the disease is not proven due to excessive expression of mutated SOD1 (where alanine substitutes glycine at position 93 SOD1 [G93A]) causes disease in the motor nerves despite an increase in SOD1 activity. Therefore, SOD1 mutations cause diseases with toxicity that interfere with function, and not because of decreased SOD1 activity. 

2. Peroxynitrite and Zinc Deficiency.

According to the gain-of-function theory, mutations in SOD1 alter enzymes, thereby increasing reactivity with abnormal substrates. For example, abnormal tyrosine nitration can damage proteins if radical peroxynitrites are used as SOD1 substrates. Free nitrotyrosine levels in the spinal cord increased in patients with ALS, both sporadic and familial types. SOD1 mutations can cause oxidative damage by interfering with the enzyme's ability to bind zinc. Because of low zinc levels, SOD1 becomes less efficient in superoxide, and tyrosine nitration levels increase. The SOD1 mutation also decreases the affinity of the enzyme with zinc, so the protein mutates and assumes zinc deficiency becomes toxic. There is also a theory that patients with sporadic ALS, normal SOD1 may experience zinc deficiency to be toxic.

3. Copper and SOD1 Aggregates.

SOD1 with zinc deficiency still requires copper even though its activity is abnormal. Two chelators remove copper from SOD1 with zinc deficient, but not from normal SOD1. Both chelators protect motor nerves from zinc SOD deficiency and may be useful in treating ALS.

4. Excitotoxicity.

Excitotoxicity is the term for neuronal injury caused by excessive glutamate stimulation induced in postsynaptic glutamate receptors such as NMDA cell surface receptors and AMPA receptors. Excessive stimulation of glutamate receptors is thought to cause calcium entries into large neurons and lead to increased nitric oxide formation, and thus, neuronal death. Glutamate levels in CSF are increased in some patients with ALS. This elevation has been associated with loss of glial excitatory amino acid transporter cells EAAT2.

5. Oxidative Stress.

Oxidative stress is associated with neurodegenerative and it is known that the accumulation of reactive oxygen species (ROS) causes cell death. As mutations in the enzyme superoxide dismutase antioxidant 1 (SOD1) gene can cause ALS, there is significant interest in the mechanism underlying the neurodegenerative process in ALS. This hypothesis is supported by findings of biochemical changes that reflect free radical damage and abnormal free radical metabolism in CSF sample tissue and post mortem ALS patients.

6. Mitochondrial Dysfunction.

Mitochondrial and biochemical morphological abnormalities have been reported in ALS patients. Mitochondria from ALS patients show high calcium levels and decreased complex I and IV respiratory chain activity, which involves the inability of energy metabolism.

7. Impaired axonal transportation.

Axon motor neuron lengths can reach up to one meter in humans, and rely on an efficient intracellular transportation system. This system consists of anterograde (slow and fast) and retrograde transportation systems, and relies on 'motor' molecules, protein kinesin complex (for anterograde) and dynein-dynactin complex (for retrograde).
In patients with ALS, mutations in the kinesin gene are known to cause neurodegenerative motor nerve diseases in humans, such as hereditary spastic paraplegia and Type 2A Charcot-Tooth disease. Mutations in the dynactin complex cause lower motor neuron disorders with paralysis of the vocal cords in humans.

8. Neurofilament aggregation.

Neurofilament proteins together with Peripherin (an intermediate filamentary protein), are present in most axonal motor neurons in the inclusion of ALS in patients. A poisonous peripheral isoform (peripherin 61), becomes toxic to motor neurons even when expressed at modest levels and is detected in the spinal cord of ALS patients.

9. Protein aggregation.

Intracytoplasmic inclusion is a characteristic of sporadic and familial ALS. However, it is still unclear whether the formation of aggregates directly causes cellular toxicity and has a key role in pathogenesis. If the aggregate is involved by the product of the neurodegeneration process, or if aggregate formation might actually be a beneficial process by being part of a defense mechanism to reduce the intracellular concentration of protein toxins.

10. Inflammatory dysfunction and non-nerve cell contribution.

Although ALS is not a primary autoimmune disorder or immune dysregulation, there is sufficient evidence that inflammatory processes and non-nerve cells may play a role in the pathogenesis of ALS. Microglial and dendritic cell activation is the leading pathologies in ALS transgenic human SOD1. Non-activated nerve cells produce inflammatory cytokines such as interleukin, COX-2, TNFa and MCP-1, and evidence of upregulation is found in CSF or spinal cord specimens in ALS patients or in vitro models.

11. Neurotrophic factors deficiency and signal pathway dysfunction. 

Decreased levels of neurotrophic factors (eg CTNF, BDNF, GDNF, and IGF-1) have been observed in post-mortem ALS patients and in in vitro models. In humans, three mutations in the VEGF gene were found to be associated with an increased risk of developing sporadic ALS, although this meta-analysis by the same author failed to show an association between VEGF haplotypes and increase the risk of ALS in humans. The final process of neuronal cell death in ALS is thought to be similar to the programmed cell death pathway (apoptosis). Biochemical markers of apoptosis are detected in the terminal stages of ALS patients.

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