期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 50, 页码 18055-18060出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1419083111
关键词
p53 transcriptional function; ChIP-chip; neurodegeneration; tauopathy; synaptic genes
资金
- NIH [P40OD018537]
- Vienna Drosophila RNAi Center
- Transgenic RNAi Project at Harvard Medical School (NIH/National Institute of General Medical Sciences) [R01GM084947]
- National Institute of Child Health and Human Development
- National Institute on Aging
- Ellison Medical Foundation
- American Health Assistance Foundation
DNA damage has been implicated in neurodegenerative disorders, including Alzheimer's disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis, we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration.
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