Mechanisms of Motor Neuron Death in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which degeneration of upper and lower motor neurons leads to progressive muscle weakness. The most common form of adult motor neuron disease in humans, ALS typically initiates in middle to late life, leading to paralysis and death within three to five years. The disease usually begins asymmetrically in one limb, most commonly the leg, and then appears to spread to involve contiguous groups of motor neurons. Approximately 10% of ALS cases are inherited in an autosomal dominant fashion. Many affected neurons in ALS patients show cytoskeletal pathology in the form of neurofilament accumulations, both within the cell bodies and in proximal axons (Carpenter 1968; Chou and Fakadej 1971; Hirano et al. 1984a, b). Motor neuron loss is also accompanied by reactive gliosis (Leigh et al. 1991), ubiquitin-positive inclusions (Leigh et al. 1991) and apparent fragmentation of the Golgi (Gonatas et al. 1992). A landmark discovery in deciphering the mechanism of the disease came from the identification of the mutations in the gene encoding cytoplasmic superoxide dismutase (SOD1) that underlie about 20% of the instances of inherited disease (Rosen et al. 1993; Siddique and Deng 1996; Andersen et al. 2000).