The epilepsy-associated protein PCDH19 undergoes NMDA receptor-dependent proteolytic cleavage and regulates the expression of immediate-early genes

Cell Rep. 2022 May 24;39(8):110857. doi: 10.1016/j.celrep.2022.110857.

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.

Keywords: CP: Microbiology; CP: Neuroscience; DEE9; LSD1; PCDH19; immediate-early genes; neurodevelopmental disorders; proteolytic cleavage; protocadherin; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins* / genetics
  • Cadherins* / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism
  • Epilepsy* / genetics
  • Epilepsy* / metabolism
  • Gene Expression Regulation
  • Genes, Immediate-Early*
  • Humans
  • Protocadherins* / genetics
  • Protocadherins* / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction

Substances

  • Cadherins
  • Chromatin
  • PCDH19 protein, human
  • Protocadherins
  • Receptors, N-Methyl-D-Aspartate