Abstract：
Protocadherin-19 (PCDH19) is a synaptic cell-adhesion molecule encoded by X-linked PCDH19, a gene linked with epilepsy. Here, we report a synapse-to-nucleus signaling pathway through which PCDH19 bridges neuronal activity with gene expression. In particular, we describe the NMDA receptor (NMDAR)-dependent proteolytic cleavage of PCDH19, which leads to the generation of a PCDH19 C-terminal fragment (CTF) able to enter the nucleus. We demonstrate that PCDH19 CTF associates with chromatin and with the chromatin remodeler lysine-specific demethylase 1 (LSD1) and regulates expression of immediate-early genes (IEGs). Our results are consistent with a model whereby PCDH19 favors maintenance of neuronal homeostasis via negative feedback regulation of IEG expression and provide a key to interpreting PCDH19-related hyperexcitability.
摘要：
原钙粘蛋白19（PCDH19）是由X连接的PCDH19编码的突触细胞粘附分子，该基因与癫痫相关。这里,我们报道了一个突触-核信号通路,PCDH19通过该通路连接神经元活性和基因表达.特别是,我们描述了PCDH19的NMDA受体（NMDAR）依赖性蛋白水解裂解，这导致产生能够进入细胞核的PCDH19C末端片段（CTF）。我们证明PCDH19CTF与染色质和染色质重塑剂赖氨酸特异性脱甲基酶1（LSD1）相关，并调节立即早期基因（IEG）的表达。我们的结果与PCDH19通过IEG表达的负反馈调节有利于维持神经元稳态的模型一致，并为解释PCDH19相关的过度兴奋提供了关键。
