Amyotrophic Lateral Sclerosis Unfolding the Toxicity of the Misfolded

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 (z1% of a prevalence of z5 per 100,000 individuals. This human cases), codon deletions or insertion in the KSP repeat disease, first described by Charcot in 1869, is charactermotif of the neurofilament NF-H gene have been identiized 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 trigrelentless disease that manifests as progressive decline gering focal initiation and then spreading of motor neuin muscular function resulting in eventual paralysis, ron degeneration in sporadic ALS remain to be elucispeech 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 damof clinical onset. The weakness, which typically begins age, excitotoxicity, mitochondrial defects, and autoimfocally and propagates, is usually associated with the munity but these could be secondary to the neurodegendegeneration of both lower motor neurons in the braineration 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 refamilial 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 environ2000). 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 common role in ALS development. pathological features such as the presence of abnormal