Amyotrophic Lateral Sclerosis Unfolding the Toxicity of the Misfolded

inherited loci map to chromosomes 2q and 15q whereas one dominant juvenile-onset locus maps to chromo-However, the genes responsible for these familial ALS-FTD and juvenile ALS cases have not yet been Amyotrophic lateral sclerosis (ALS) is one of the most identified. common adult-onset neurogenerative diseases, having In a small number of sporadic ALS patients (‫%1ف‬ of a prevalence of ‫5ف‬ per 100,000 individuals. This human cases), codon deletions or insertion in the KSP repeat disease, first described by Charcot in 1869, is character-motif of the neurofilament NF-H gene have been identi-ized by the selective degeneration of motor neurons, fied (for review see Cleveland, 1999). No such NF-H the large nerve cells connecting the brain to the spinal mutants have been detected in over 1000 control DNA cord and from the spinal cord to muscles, that control samples. The combined data suggest that NF-H variants muscle movement. The loss of motor neurons leads may represent risk factors for ALS disease. to progressive atrophy of skeletal muscles. ALS is a For the vast majority of ALS cases, the factors trig-relentless disease that manifests as progressive decline gering focal initiation and then spreading of motor neu-in muscular function resulting in eventual paralysis, ron degeneration in sporadic ALS remain to be eluci-speech deficits and, ultimately, death due to respiratory dated. Various hypotheses have been suggested as failure in the majority of ALS patients within 2 to 5 years potential contributors of disease such as oxidative dam-of clinical onset. The weakness, which typically begins age, excitotoxicity, mitochondrial defects, and autoim-focally and propagates, is usually associated with the munity but these could be secondary to the neurodegen-degeneration of both lower motor neurons in the brain-eration process. The " virus hypothesis " as primary stem and spinal cord, and upper motor neurons in the cause of ALS is now being revisited in light of a recent cerebral cortex. Approximately 10% of ALS patients are report of enterovirus (EV) nucleic acids detected by re-familial cases. The majority of ALS cases are sporadic verse transcriptase-PCR in the spinal cord of a high (90%) with no known genetic component. While current percentage of patients with sporadic ALS (Berger et al., evidence suggests that multiple genetic and environ-2000). More studies are needed to confirm these results mental factors may be implicated in ALS pathogenesis, and to demonstrate that EV sequences can play a causal both sporadic and familial ALS cases share …