Our new preprint in collaboration with @keith_caldecott lab linking PARP hyperactivation with DNA damage-induced seizures and shortened lifespan.
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 we show 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.