p53 prevents neurodegeneration by regulating synaptic genes

Significance The transcription factor p53 plays a critical role in the cellular response to DNA damage and has thus been studied intensively in oncogenesis research. However, the role that p53 plays in the response of postmitotic neurons to cellular stress has received less attention. Here we describe an unexpected neuroprotective role for p53 in an in vivo model of tau-mediated neurodegeneration relevant to Alzheimer's disease and related disorders. Further, we identify synaptic function as a novel target pathway for p53 in aging neurons, consistent with the growing evidence for synaptic pathology as an early event in neurodegenerative disease. Our study defines mechanistically a new, conserved role for p53 in protecting postmitotic neurons from degeneration during aging and disease. 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.