Cellular and molecular mechanisms of neuronal degeneration: Amyotrophic lateral sclerosis, parkinsonism-demantia, and Alzheimer disease.

Hyperendemic Pacific foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) represent naturally occurring models of late-onset chronic degenerative diseases that occur in different cultures, in different ecological zones, and among genetically divergent populations. These diseases occur among the Chamorros of the Mariana Islands, among the Auyu and Jakai of southern West New Guinea, and among the Japanese from the Kill Peninsula of Honshu Island. Accumulating evidence supports the hypothesis that a defect in mineral metabolism may be etiologically involved. Toxic and essential elements, such as calcium aluminum, and silicon cross the blood-brain barrier, deposit in affected neurons, and disrupt the axonal transport system, resulting in the abnormal copolymerization of cytoskeletal and amyloid β-proteins in neurons. The pathological accumulation of these and other proteins into neurofibrillary tangles (the hallmark neuropathological lesion) causes neuronal dysfunction and death. Recent immunocytochemical and biochemical studies indicate that the amyloid β-protein in Guamanian PD has an identical amino acid sequence, a similar N-terminus heterogeneity (variation in polypeptide length), and a similar immunoreactivity to those found in Alzheimer disease, suggesting a common mechanism of pathogenesis. Investigations are now underway to determine whether the abnormal accumulation of amyloid β-protein in neurons of Guamanian patients with ALS and PD is the result of an aberrant post-translational modification of a larger precursor protein, an additional copy of the amyloid gene, or an impairment of amyloid catabolism all of which may be mediated by metal-enzyme or metal-gene interactions. The abnormal copolymerization of other proteins such as neurofilament, microtubule-associated protein tau, and ubiquitin in affected neurons suggests their interrelationship in the disease process.