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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):18055-60. doi: 10.1073/pnas.1419083111. Epub 2014 Dec 1.

p53 prevents neurodegeneration by regulating synaptic genes.

Author information

1
Departments of Pathology and.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
3
Division of Genetics and Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115; Broad Institute of MIT and Harvard, Howard Hughes Medical Institute, Cambridge, MA 02142; and.
4
Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115.
5
Departments of Pathology and mel_feany@hms.harvard.edu.

Abstract

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.

KEYWORDS:

ChIP-chip; neurodegeneration; p53 transcriptional function; synaptic genes; tauopathy

PMID:
25453105
PMCID:
PMC4273405
DOI:
10.1073/pnas.1419083111
[Indexed for MEDLINE]
Free PMC Article

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