Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1 Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1 Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.

Defects in DNA strand break repair can trigger seizures that are often intractable and life-threatening. However, the molecular mechanism/s by which unrepaired DNA breaks trigger seizures are unknown. Here, we show that hyperactivity of the DNA break sensor protein poly(ADP-ribose) polymerase-1 is widespread in DNA single-strand break repair defective XRCC1-mutant mouse brain, including the hippocampus and cortex. We demonstrate elevated seizure-like activity in XRCC1-mutant hippocampus in vitro and increased seizures in vivo, and weshow that Parp1 deletion reduces or prevents both. We also show that the increased seizures in Xrcc1 mutant mice result in juvenile mortality, and that Parp1 deletion extends the lifespan of these mice up to 25-fold. Parp1 hyperactivation is thus a major molecular mechanism by which unrepaired endogenous DNA strand breaks trigger disease pathology, including neurological seizures and death. These data implicate inhibitors of PARP activity as a possible therapeutic approach for the treatment of single-strand break induced neurodegenerative disease. DNA single-strand breaks (SSBs) are the commonest lesions arising in cells and can result directly from damage to deoxyribose, indirectly as an obligate intermediate of DNA base or ribonucleotide excision repair, and as abortive intermediates of topoisomerase activity. SSBs are rapidly detected by the enzymes poly(ADP-ribose)polymerase-1 (PARP1) and/or poly(ADP-ribose) polymerase-2 (PARP2); two enzymes that bind to DNA breaks and subsequently modify themselves and other proteins at the site of the break with polymeric chains of ADP-ribose (1-3). This polymer, denoted poly(ADP-ribose), triggers recruitment the DNA single-strand break repair (SSBR) scaffold protein XRCC1 and its protein partners which subsequently can process any damaged DNA termini at the break and complete SSBR (4-6).If not repaired rapidly, SSBs can result in replication fork stalling and/or collapse (7-10) and can block the progression of RNA polymerases during gene transcription (11,12). Moreover, mutations in proteins involved in SSBR are associated in humans with cerebella ataxia, neurodevelopmental defects, and episodic seizures (13)(14)(15)(16)(17)(18)(19). To date, all of the identified SSBR-defective human diseases are mutated in either