Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F21%3A00544973" target="_blank" >RIV/68378050:_____/21:00544973 - isvavai.cz</a>
Result on the web
<a href="https://www.embopress.org/doi/full/10.15252/embr.202051851" target="_blank" >https://www.embopress.org/doi/full/10.15252/embr.202051851</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.15252/embr.202051851" target="_blank" >10.15252/embr.202051851</a>
Alternative languages
Result language
angličtina
Original language name
Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures
Original language description
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 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 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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Embo Reports
ISSN
1469-221X
e-ISSN
1469-3178
Volume of the periodical
22
Issue of the periodical within the volume
5
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
e51851
UT code for WoS article
000645944000001
EID of the result in the Scopus database
—