Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures
Emilia Komulainen1, Jack Badman1,2, Stephanie Rey2
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
EMBO Reports
|May 1, 2021
Summary
Defects in DNA single-strand break repair (SSBR) cause neurological issues. Aberrant Parp1 activity at unrepaired breaks triggers lethal seizures in mice, suggesting PARP inhibition as a therapy for neurological diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Defects in DNA single-strand break repair (SSBR) are associated with neurological dysfunction.
- The precise mechanisms linking SSBR defects to neurological dysfunction are not well understood.
Purpose of the Study:
- To investigate the role of Poly(ADP-ribose) polymerase 1 (Parp1) hyperactivity in neurological dysfunction caused by Xrcc1 deficiency.
- To explore the potential of PARP inhibition as a therapeutic strategy for SSBR-related neurological disorders.
Main Methods:
- Conditional deletion of the Xrcc1 gene in mice (Xrcc1Nes-Cre).
- Electrophysiological recordings and synaptic imaging in ex vivo hippocampus and in vitro neurons.
- Assessment of Parp1 activity, seizure activity, presynaptic calcium signaling, and lifespan.
Main Results:
- Hyperactivity of Parp1 in Xrcc1-deficient mice led to lethal seizures and reduced lifespan.
- Aberrant Parp1 activation triggered seizure-like activity and deregulated presynaptic calcium signaling.
- Parp1 inhibition or deletion prevented these neurological defects and extended lifespan.
Conclusions:
- Aberrant Parp1 activity at unrepaired single-strand breaks can trigger lethal seizures.
- Targeting PARP offers a potential therapeutic avenue for hereditary neurological diseases linked to SSBR defects.
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