Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. 4 samples: tau vs. control

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Peter Park

PROVIDER: E-GEOD-40418 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

p53 prevents neurodegeneration by regulating synaptic genes.

Merlo Paola P Frost Bess B Peng Shouyong S Yang Yawei J YJ Park Peter J PJ Feany Mel M

Proceedings of the National Academy of Sciences of the United States of America 20141201 50

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, syn ...[more]

PMID: 25453105

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Project description:Sustained or repeated exposure to sedating drugs such as alcohol triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Drug-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most that may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct drugs. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol. A total of six samples. Two H4Ac ChIP-chip biological replicates from heads of Drosophila (untreated, IP/input), two H4Ac ChIP-chip biological replicates from heads of Drosophila sedated with benzyl alcohol (IP_treated/IP_control), and two H4Ac ChIP-chip biological replicates from heads of Drosophila sedated with ethanol (IP_treated/IP_control) are included.

Dataset Information

P53 prevents neurodegeneration by regulating synaptic genes

Publications

p53 prevents neurodegeneration by regulating synaptic genes.

Similar Datasets

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