Developmental mechanisms in the pathogenesis of neurodegenerative diseases

Cellular genes that are mutated in neurodegenerative diseases code for prot eins that are expressed throughout neural development. Genetic analysis sug gests that these genes are essential for a broad range of normal neurodevel opmental processes. The proteins they code for interact with numerous other cellular proteins that are components of signaling pathways involved in pa tterning of the neural tube and in regional specification of neuronal subty pes. Further, pathogenetic mutations of these genes can cause progressive, sublethal alterations in the cellular homeostasis of evolving regional neur onal subpopulations, culminating in late-onset cell death. Therefore, as a consequence of the disease mutations, targeted cell populations may retain molecular traces of abnormal interactions with disease-associated proteins by exhibiting changes in a spectrum of normal cellular functions and enhanc ed vulnerability to a host of environmental stressors. These observations s uggest that the normal functions of these disease-associated proteins are t o ensure the fidelity and integration of developmental events associated wi th the progressive elaboration of neuronal subtypes as well as the maintena nce of mature neuronal populations during adult life. The ability to identi fy alterations within vulnerable neuronal precursors present in pre-symptom atic individuals prior to the onset of irrevocable cellular injury may help foster the development of effective therapeutic interventions using evolvi ng pharmacologic, gene and stem cell technologies. (C) 2001 Elsevier Scienc e Ltd. All rights reserved.