The "somatic-spread" hypothesis for sporadic neurodegenerative diseases

The major neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) share in common a mostly sporadic occurrence, a focal onset of pathology, and spread from the initial site of injury to adjacent regions of the nervous system. The sporadic nature and focal onset of these diseases can be explained either by somatic mutations (arising in either of two models of cell lineage) or environmental agents, both of which affect a small number of neurons. The genetic or environmental agent then changes the conformation of a vital protein in these neurons. Spread of the diseases occurs by the misfolded proteins being transferred to adjacent neurons. Clinical and pathological details of one neurodegenerative disorder, amyotrophic lateral sclerosis, are presented to show how the pathogenesis of a typical neurodegenerative disease can be explained by this “somatic-spread” hypothesis. Ultrasensitive techniques will be needed to detect the initiating genetic or environmental differences that are predicted to be present in only a few cells.