Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Embo Reports

ISSN

1469-221X

e-ISSN

1469-3178

Svazek periodika

22

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

e51851

Kód UT WoS článku

000645944000001

EID výsledku v databázi Scopus

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