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

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.
Laura Gerosa 1,  Sara Mazzoleni 2,  Francesco Rusconi 3,  Alessandra Longaretti 3,  Elly Lewerissa 4,  Silvia Pelucchi 5,  Luca Murru 6,  Serena Gea Giannelli 7,  Vania Broccoli 8,  Elena Marcello 5,  Nael Nadif Kasri 4,  Elena Battaglioli 2,  Maria Passafaro 6,  Silvia Bassani 9
Affiliations

Affiliations

  • 1 Institute of Neuroscience, CNR, 20854 Vedano al Lambro, Italy.
  • 2 Institute of Neuroscience, CNR, 20854 Vedano al Lambro, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milano, Italy.
  • 3 Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milano, Italy.
  • 4 Donders Institute for Brain, Cognition, and Behaviour, Department of Human Genetics, Department of Human Genetics Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
  • 5 Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy.
  • 6 Institute of Neuroscience, CNR, 20854 Vedano al Lambro, Italy; NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, 20126 Milano, Italy.
  • 7 Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy.
  • 8 Institute of Neuroscience, CNR, 20854 Vedano al Lambro, Italy; Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy.
  • 9 Institute of Neuroscience, CNR, 20854 Vedano al Lambro, Italy; NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, 20126 Milano, Italy. Electronic address: silvia.bassani@in.cnr.it.
PMID: 35613587 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.

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