Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
R01 NS037956
NINDS NIH HHS - United States
MR/P010121/1
Medical Research Council - United Kingdom
BB/S00310X/1
Biotechnology and Biological Sciences Research Council - United Kingdom
694996
European Research Council - International
BB/K019015/1
Biotechnology and Biological Sciences Research Council - United Kingdom
PubMed
33932076
PubMed Central
PMC8097344
DOI
10.15252/embr.202051851
Knihovny.cz E-zdroje
- Klíčová slova
- DNA strand break, XRCC1, neurodegeneration, poly(ADP-ribose) polymerase, seizures,
- MeSH
- DNA vazebné proteiny * genetika metabolismus MeSH
- DNA MeSH
- myši MeSH
- neurony metabolismus MeSH
- oprava DNA genetika MeSH
- poly-ADP-ribóza-polymeráza 1 genetika metabolismus MeSH
- vápník * MeSH
- záchvaty genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny * MeSH
- DNA MeSH
- poly-ADP-ribóza-polymeráza 1 MeSH
- vápník * MeSH
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 (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.
Department of Genetics St Jude Children's Research Hospital Memphis TN USA
Genome Damage and Stability Centre School of Life Sciences University of Sussex Brighton UK
Sussex Neuroscience School of Life Sciences University of Sussex Brighton UK
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XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair