Amyotrophic lateral sclerosis: Recent insights from genetics and transgenic mice

Introduction and Clinical Pathology Amyotrophic lateral sclerosis (ALS) is a prototypic, agedependent neurodegenerative disorder. It typically afflicts individuals in middle adult life, leading to paralysis and death within 3 to 5 years (Williams and Windebank, 1991). The disease usually begins asymmetrically and distally in one limb, most commonly the leg, and then appears to spread within the neuraxis to involve contiguous groups of motor neurons. Pathologically, ALS is distinguished by atrophy and death of the affected neurons, with dissolution of both cytoplasm and nuclei. The motor neuron death process appears to be cell autonomous; autopsy studies reveal no evidence that other cell types participate in killing motor neurons. Many affected neurons demonstrate evidence of cytoskeletal pathology in the form of accumulations of neurofllaments, both within the neuronal cell body and in axons. Aggregates of ubiquitinated, unidentified proteins are also seen, as is subtle proliferation of glial cells (Leigh and Swash, 1991). Recent investigations have implicated oxidative cytotoxicity in the pathogenesis of a familial form of ALS (FALS). This review considers the evidence that this disease arises from oxidative and excitotoxic injury to critical subcellular targets in motor neurons and summarizes current hypotheses concerning the mechanism of motor neuron death in ALS.