embr.202051851.pdf (1.69 MB)
Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures
journal contribution
posted on 2023-06-10, 00:56 authored by Emilia KomulainenEmilia Komulainen, Jack Badman, Stephanie Rey, Stuart Rulten, Limei Ju, Kate FennellKate Fennell, Ilona Kalasova, Kristyna Ilievova, Peter J McKinnon, Hana Hanzlikova, Kevin StarasKevin Staras, Keith CaldecottKeith CaldecottDefects 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 (Xrcc1Nes-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 Xrcc1-defective 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 Xrcc1Nes-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.
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Publication status
- Published
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- Published version
Journal
EMBO ReportsISSN
1469-221XPublisher
WileyExternal DOI
Issue
5Volume
22Page range
1-12Article number
a51851Event location
EnglandDepartment affiliated with
- Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-09-10First Open Access (FOA) Date
2021-09-10First Compliant Deposit (FCD) Date
2021-09-10Usage metrics
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