Neuropathology of amyotrophic lateral sclerosis: new perspectives on an old disease

Recent discoveries on linkage of the gene mutation of an enzyme, copper/zinc superoxide dismutase 1 (SOD-1), to familial amyotrophic lateral sclerosis (ALS) (which constitutes about 1% of all ALS cases) and several transgenic mouse models of ALS have shed light on potential pathogenetic processes involved in this disease. Any speculation as to the pathogenesis of ALS must reflect the unique neurobiology of motor neurons. The most distinctive aspects of motor neurons are their asymmetry, large size, and enormously elongated and thick axons. These characteristics also contribute to their vulnerability to ALS. The determinants of these unique properties are the intermediate cytoskeletal filaments, and the neurofilaments of motor neurons. This characteristic is not exclusive to motor neurons and is shared with other neurons with long axons, including some sensory neurons that are also involved in ALS. The histopathology of the early stages of ALS overwhelmingly suggests that accumulation and aggregation of neurofilaments within motor neurons is intimately related to the morphogenesis of the unique cytoplasmic inclusions, and plays a central role in the pathogenesis of the disease. Understanding of the causal relationship and the morphogenesis of inclusion bodies is critical in any attempt to reverse this complex disease process, which potentially involves the neurotoxic effects of free radicals (nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, etc) on neurofilaments. By emphasizing the unique make-up of motor neurons, this review intends to reevaluate and reinterpret the basic neuropathology of ALS in the light of recent molecular genetic-data.