Mechanisms underlying neural cell death in neurodegenerative diseases: Alterations of a developmentally-mediated cellular rheostat

Genes associated with neurodegenerative diseases are normally expressed throughout neural development and are essential for the elaboration and maintenance of neuronal subpopulations. Disease-causing mutations can compromise defined subsets of these neural specification events in subtle ways that initially lead to impairments in the cellular homeostasis of evolving regional neuronal subpopulations, and adult-onset cell death from normally non-lethal environmental stressors. Neurodegenerative diseases may, therefore, represent an emerging class of developmental disorders characterized by novel biological responses to subthreshold neurodevelopmental abnormalities that impair targeted neuronal biosynthetic pathways without causing obvious developmental deficits. This developmental model of pathogenesis predicts that it will soon be possible to identify these dysfunctional pathways prior to the occurrence of irreversible cellular injury, and to successfully intervene using innovative neuroprotective and neural regenerative strategies.