Trends in Neurosciences
Volume 23, Issue 12, 1 December 2000, Pages 599-605
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Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat

https://doi.org/10.1016/S0166-2236(00)01705-7Get rights and content

Abstract

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.

Section snippets

Regulation of regional neurogenesis and abnormalities in associated developmental processes that predispose to cell death

The mechanisms governing the genesis of regional neuronal subtypes are still largely unknown. There is increasing recognition that the elaboration and maintenance of these regional neuronal subpopulations are determined by the interplay of soluble signals, gradient morphogens and transcriptional regulators that are expressed during progressive stages of neural induction, patterning of the neuraxis and neurogenesis and endow these evolving subpopulations with unique cellular properties24 (Fig. 1

Role of presenilin mutations in altering the viability and cellular homeostasis of neural developmental species

Impairments in the cellular homeostasis of mutant neural precursor and mature neuronal species may be mediated by a variety of developmental mechanisms (Fig. 2). PS1 directly interacts with anti-apoptotic bcl2 family members that normally preserve the viability of neural stem/progenitor (bcl2) and nascent neuroblast (bcl-xL) subpopulations during sequential stages of developmental apoptosis42., 43.. PS1–/– mice exhibit massive neuronal death during embryonic stages of neurogenesis, whereas

Acknowledgements

The authors thank B. Shapiro for artistic expertise, R. Sanchez for performing the protein database searches and K.S. Marder and Z. Kaprielian for critical commentaries. The authors research was supported by grants from the NINDS, NIH. We sincerely regret the fact that space limitations have prevented us from citing the many outstanding experimental studies that have contributed to our evolving view of the relationship between development and neurodegeneration.

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