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ATM dependent apoptosis in the nervous system
1Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Abstract:
Ataxia-telangiectasia is a human syndrome resulting from mutations of the ATM protein kinase that is characterized by radiation sensitivity and neurodegeneration. Although neuroprotective, the molecular details of ATM function in the nervous system are uncertain. However, in the mouse, Atm is essential for ionizing radiation-induced apoptosis in select postmitotic populations of the developing nervous system. Atm-dependent apoptosis in the nervous system also requires p53, consistent with the well-established link of p53 as a major substrate of ATM. Furthermore, the proapoptotic effector Bax is also required for most, but not all, Atm-dependent apoptosis. Therefore, after DNA damage in the developing nervous system, Atm initiates a p53-dependent apoptotic cascade in differentiating neural cells. Together, these data suggest ATM-dependent apoptosis may be important for elimination of neural cells that have accumulated genomic damage during development, thus preventing dysfunction of these cells later in life.
Insights
Ataxia-telangiectasia (ATM) gene mutations cause neurodegeneration. ATM kinase is crucial for eliminating damaged neural cells during development via p53-dependent apoptosis, preventing later-life dysfunction.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Ataxia-telangiectasia (A-T) is a human genetic disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene.
- ATM protein kinase plays a role in DNA damage response, radiation sensitivity, and neurodegeneration, but its precise function in the nervous system is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms of ATM kinase function in the developing nervous system.
- To elucidate the role of ATM in neuronal apoptosis following DNA damage.
Main Methods:
- Utilized mouse models to study Atm-dependent apoptosis in the developing nervous system after ionizing radiation exposure.
- Examined the involvement of p53 and Bax in ATM-mediated apoptotic pathways.
Main Results:
- In mice, Atm is essential for ionizing radiation-induced apoptosis in specific postmitotic neural cell populations.
- ATM-dependent apoptosis in the nervous system requires both p53 and, for the most part, the proapoptotic effector Bax.
- ATM initiates a p53-dependent apoptotic cascade in differentiating neural cells following DNA damage.
Conclusions:
- ATM-dependent apoptosis is critical for removing neural cells with accumulated genomic damage during development.
- This process may prevent nervous system dysfunction later in life, suggesting a neuroprotective role for ATM in development.