Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
复制标题
DOI：
10.15252/embr.202051851
复制
发表时间：
2021-05-05
期刊：
影响因子：
7.7
通讯作者：
Caldecott KW
中科院分区：
文献类型：
--
作者：
Komulainen E;Badman J;Rey S;Rulten S;Ju L;Fennell K;Kalasova I;Ilievova K;McKinnon PJ;Hanzlikova H;Staras K;Caldecott KW
DNA单链断裂修复(SSBR)中的缺陷与神经功能障碍有关，但其潜在机制仍不清楚。在这里，我们证明了在中心SSBR蛋白Xrcc1有条件缺失(Xrcc1Nes-Cre)的小鼠中，DNA链断裂传感器蛋白PARP1的过度活动会导致致命的癫痫发作和寿命缩短。使用电生理记录和突触成像方法，我们证明了异常的PARP1激活在体外触发了Xrcc1缺陷海马区的癫痫样活动，并在体外激活了分离的海马神经元中失控的突触前钙信号。此外，我们表明，这些缺陷可以通过抑制或缺失PARP1来防止，并且在PARP1缺失的情况下，Xrcc1Nes-CRE小鼠的寿命大大延长。这是第一个证据表明，在未修复的SSB上，PARP1的异常活性可以触发致命的癫痫发作，这突显了PARP抑制是遗传性神经疾病的一种可能的治疗方法。在XrCC1缺陷脑中，未修复的DNA单链断裂处PARP1活性过高会导致突触钙信号异常、癫痫发作和寿命缩短。这些效应可以通过抑制PARP1来防止，从而揭示了治疗人类神经疾病的可能性。
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. Excessive PARP1 activity at unrepaired DNA single‐strand breaks in Xrcc1‐defective brain causes aberrant synaptic calcium signaling, seizures, and shortened lifespan. These effects are prevented by Parp1 inhibition, revealing possibilities for the treatment of human neurological disease.