TY - JOUR
T1 - Developmental mechanisms in the pathogenesis of neurodegenerative diseases
AU - Mehler, Mark F.
AU - Gokhan, Solen
N1 - Funding Information:
The authors wish to thank E.H. Koo, M.H. Polymeropoulos, A.H. Schapira, K.S. Marder, D.S. Faber, M.V.L. Bennett, D. Housman, D.P. Purpura and J.A. Kessler for continuing support, encouragement and critical commentaries. We also thank B. Shapiro for outstanding artistic expertise. Experimental studies cited from the author's laboratory were supported by grants from the NINDS, NIH.
PY - 2001
Y1 - 2001
N2 - Cellular genes that are mutated in neurodegenerative diseases code for proteins that are expressed throughout neural development. Genetic analysis suggests that these genes are essential for a broad range of normal neurodevelopmental processes. The proteins they code for interact with numerous other cellular proteins that are components of signaling pathways involved in patterning of the neural tube and in regional specification of neuronal subtypes. Further, pathogenetic mutations of these genes can cause progressive, sublethal alterations in the cellular homeostasis of evolving regional neuronal 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 enhanced vulnerability to a host of environmental stressors. These observations suggest that the normal functions of these disease-associated proteins are to ensure the fidelity and integration of developmental events associated with the progressive elaboration of neuronal subtypes as well as the maintenance of mature neuronal populations during adult life. The ability to identify alterations within vulnerable neuronal precursors present in pre-symptomatic individuals prior to the onset of irrevocable cellular injury may help foster the development of effective therapeutic interventions using evolving pharmacologic, gene and stem cell technologies. Copyright (C) 2001 Elsevier Science Ltd.
AB - Cellular genes that are mutated in neurodegenerative diseases code for proteins that are expressed throughout neural development. Genetic analysis suggests that these genes are essential for a broad range of normal neurodevelopmental processes. The proteins they code for interact with numerous other cellular proteins that are components of signaling pathways involved in patterning of the neural tube and in regional specification of neuronal subtypes. Further, pathogenetic mutations of these genes can cause progressive, sublethal alterations in the cellular homeostasis of evolving regional neuronal 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 enhanced vulnerability to a host of environmental stressors. These observations suggest that the normal functions of these disease-associated proteins are to ensure the fidelity and integration of developmental events associated with the progressive elaboration of neuronal subtypes as well as the maintenance of mature neuronal populations during adult life. The ability to identify alterations within vulnerable neuronal precursors present in pre-symptomatic individuals prior to the onset of irrevocable cellular injury may help foster the development of effective therapeutic interventions using evolving pharmacologic, gene and stem cell technologies. Copyright (C) 2001 Elsevier Science Ltd.
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U2 - 10.1016/S0301-0082(00)00052-6
DO - 10.1016/S0301-0082(00)00052-6
M3 - Review article
C2 - 11115729
AN - SCOPUS:0035207082
SN - 0301-0082
VL - 63
SP - 337
EP - 363
JO - Progress in Neurobiology
JF - Progress in Neurobiology
IS - 3
ER -