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bioRxiv · 10.1101/431916

Poly(ADP-ribose) Polymerase-1 Hyperactivity at DNA Single-Strand Breaks Triggers Seizures and Shortened Lifespan

Komulainen, E.·Rey, S.·Rulten, S.·Ju, L.·McKinnon, P.·Staras, K.·Caldecott, K.
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Abstract

Defects in DNA single-strand break repair result in cerebellar ataxia which in Xrcc1Nes-Cre mice 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 hippocampus ex vivo and aberrant presynaptic calcium signalling in isolated hippocampal neurons in 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 in XRCC1-mutated neurodegenerative disease. SummaryPARP1 activity and presynaptic Ca2+ signalling

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Komulainen, E., Rey, S., Rulten, S., Ju, L., McKinnon, P., Staras, K., Caldecott, K.. 2018-10-01. Poly(ADP-ribose) Polymerase-1 Hyperactivity at DNA Single-Strand Breaks Triggers Seizures and Shortened Lifespan. https://doi.org/10.1101/431916

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