Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications.
Amyotrophic lateral sclerosis (ALS) is a late-onset progressive degeneration of motor neurons occurring both as a sporadic and a familial disease. The etiology of ALS remains unknown, but one fifth of instances are due to specific gene defects, the best characterized of which is point mutations in the gene coding for Cu/Zn superoxide dismutase (SOD1). Because sporadic and familial ALS affect the same neurons with similar pathology, it is hoped that understanding these gene defects will help in devising therapies effective in both forms. A wealth of evidence has been collected in rodents made transgenic for mutant SOD1, which represent the best available models for familial ALS. Mutant SOD1 likely induces selective vulnerability of motor neurons through a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities and defective axonal transport, excitotoxicity, inadequate growth factor signaling, and inflammation. Damage within motor neurons is enhanced by noxious signals originating from nonneuronal neighboring cells, where mutant SOD1 induces an inflammatory response that accelerates disease progression. The clinical implication of these findings is that promising therapeutic approaches can be derived from multidrug treatments aimed at the simultaneous interception of damage in both motor neurons and nonmotor neuronal cells.
Cozzolino
Mauro
M
Fondazione Santa Lucia IRCCS, Rome, Italy.
Ferri
Alberto
A
Carrì
Maria Teresa
MT
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D016923:Cell Death; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics
D013482:Superoxide Dismutase