title: p53 prevents neurodegeneration by regulating synaptic genes.
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.
authors.affiliation: Departments of Pathology and.
authors.forename: Paola
authors.initials: P
authors.lastname: Merlo
authors.affiliation: Departments of Pathology and.
authors.forename: Bess
authors.initials: B
authors.lastname: Frost
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Yawei J
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Departments of Pathology and mel_feany@hms.harvard.edu.
authors.forename: Mel
authors.initials: M
authors.lastname: Feany
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000502:physiology; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D063990:Gene Ontology; D007150:Immunohistochemistry; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D013569:Synapses / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D016875:tau Proteins / Q000009:adverse effects
chemical_list: D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; C474203:p53 protein, Drosophila; D016875:tau Proteins
keywords: ChIP-chip; neurodegeneration; p53 transcriptional function; synaptic genes; tauopathy