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

Genes associated with neurodegenerative diseases are normally expressed thr oughout neural development and are essential for the elaboration and mainte nance of neuronal subpopulations, Disease-causing mutations can compromise defined subsets of these neural specification events in subtle ways that in itially lead to impairments in the cellular homeostasis of evolving regiona l neuronal subpopulations, and adult-onset cell death from normally non-let hal environmental stressors, Neurodegenerative diseases may, therefore, rep resent an emerging class of developmental disorders characterized by novel biological responses to subthreshold neurodevelopmental abnormalities that impair targeted neuronal biosynthetic pathways without causing obvious deve lopmental 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 interve ne using innovative neuroprotective and neural regenerative strategies.