[HTML][HTML] Amyotrophic lateral sclerosis: unfolding the toxicity of the misfolded

JP Julien - Cell, 2001 - cell.com
Cell, 2001cell.com
Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset neurogenerative
diseases, having a prevalence of∼ 5 per 100,000 individuals. This human disease, first
described by Charcot in 1869, is characterized by the selective degeneration of motor
neurons, the large nerve cells connecting the brain to the spinal cord and from the spinal
cord to muscles, that control muscle movement. The loss of motor neurons leads to
progressive atrophy of skeletal muscles. ALS is a relentless disease that manifests as …
Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset neurogenerative diseases, having a prevalence of∼ 5 per 100,000 individuals. This human disease, first described by Charcot in 1869, is characterized by the selective degeneration of motor neurons, the large nerve cells connecting the brain to the spinal cord and from the spinal cord to muscles, that 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. The weakness, which typically begins focally and propagates, is usually associated with the degeneration of both lower motor neurons in the brainstem and spinal cord, and upper motor neurons in the cerebral cortex. Approximately 10% of ALS patients are familial cases. The majority of ALS cases are sporadic (90%) with no known genetic component. While current evidence suggests that multiple genetic and environmental factors may be implicated in ALS pathogenesis, both sporadic and familial ALS cases share common pathological features such as the presence of abnormal neurofilamentous accumulations in degenerating motor neurons.
The discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) eight years ago in subsets of familial cases provided much hope for quick development of therapies, and it directed most ALS research on elucidating the mechanism of SOD1-mediated disease. Yet, understanding the toxicity of SOD1 mutants has been surprisingly challenging. Important efforts have also been devoted to clarifying the role of neurofilaments in ALS pathogenesis. Again, studies with transgenic mice yielded complex results. Here, I shall review the current hypotheses on mechanisms of ALS disease with emphasis on toxicity of SOD1 mutants and on cytoskeletal abnormalities.
cell.com