Aberrant PARP1 Activity Couples DNA Breaks to Deregulated Presynaptic Calcium Signalling and Lethal Seizures

AbstractDefects in DNA single-strand break repair result in cerebellar ataxia which inXrcc1Nes-Cremice is promoted by hyperactivity of the DNA strand break sensor protein, Parp1. Here, we show that Parp1 hyperactivity extends beyond the cerebellum in Xrcc1-defective brain, resulting in lethal seizures and shortened lifespan. We demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampusex vivoand aberrant presynaptic calcium signalling in isolated hippocampal neuronsin vitro.Moreover, we show that these defects are prevented by Parp1 inhibition and/or deletion. Collectively, these data identify aberrant Parp1 activity at unrepaired DNA breaks as a cell-autonomous source of deregulated presynaptic calcium signalling, and highlight PARP inhibition as a possible therapeutic approach inXRCC1-mutated neurodegenerative disease.SummaryPARP1 activity and presynaptic Ca2+signalling