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Neuronal life and death: an essential role for the p53 family
F D Miller1, C D Pozniak, G S Walsh
1Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, Canada H3A 2B4. mdfm@musica.mcgill.ca
Abstract:
Recent evidence indicates that the p53 tumor suppressor protein, and its related family member, p73, play an essential role in regulating neuronal apoptosis in both the developing and injured, mature nervous system. In the developing nervous system, they do so by regulating naturally-occurring cell death in neural progenitor cells and in postmitotic neurons, acting to ensure the apoptosis of cells that either do not appropriately undergo the progenitor to postmitotic neuron transition, or that fail to compete for sufficient quantities of trophic support. Somewhat surprisingly, in developing postmitotic neurons, p53 plays a proapoptotic role, while a naturally-occurring, truncated form of p73, DeltaNp73, antagonizes p53 and plays an anti-apoptotic role. In the mature nervous system, numerous studies indicate that p53 is essential for the neuronal death in response to a variety of insults, including DNA damage, ischemia and excitotoxicity. It is likely that all of these insults culminate in DNA damage, which may well be a common trigger for neuronal apoptosis. In this regard, the signaling pathways that are responsible for triggering p53-dependent neuronal apoptosis are starting to be elucidated, and involve cell cycle deregulation and activation of the JNK pathway. Finally, accumulating evidence indicates that p53 is perturbed in the CNS in a number of neurodegenerative disorders, leading to the hypothesis that longterm oxidative damage and/or excitotoxicity ultimately trigger p53-dependent apoptosis in the chronically degenerating nervous system.
Insights
The p53 and p73 proteins regulate neuronal cell death in developing and mature nervous systems. DNA damage, ischemia, and excitotoxicity trigger p53-dependent apoptosis, implicated in neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Death Research
Background:
- The p53 and p73 protein families are crucial regulators of apoptosis.
- Neuronal apoptosis plays a vital role in nervous system development and response to injury.
- Dysregulation of these proteins is implicated in neurodegenerative diseases.
Purpose of the Study:
- To elucidate the roles of p53 and p73 in neuronal apoptosis during nervous system development and in mature, injured brains.
- To investigate the triggers and signaling pathways of p53-dependent neuronal apoptosis.
- To explore the involvement of p53 in neurodegenerative disorders.
Main Methods:
- Review of existing evidence on p53 and p73 function in neuronal apoptosis.
- Analysis of signaling pathways involved in p53-mediated neuronal cell death, including DNA damage response, cell cycle deregulation, and JNK pathway activation.
- Examination of p53 perturbation in the central nervous system (CNS) in neurodegenerative conditions.
Main Results:
- In developing neurons, p53 is proapoptotic, while DeltaNp73 is anti-apoptotic, regulating progenitor cell death and neuronal survival.
- In mature neurons, p53 mediates apoptosis induced by DNA damage, ischemia, and excitotoxicity.
- Evidence suggests DNA damage is a common trigger for p53-dependent neuronal apoptosis.
- Signaling pathways involving cell cycle deregulation and JNK activation are implicated.
Conclusions:
- p53 and p73 are essential for programmed neuronal cell death in both developing and mature nervous systems.
- p53-dependent apoptosis, triggered by DNA damage, is a key mechanism in neuronal injury and potentially in neurodegeneration.
- Further research into these pathways may offer therapeutic targets for neurodegenerative diseases.