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
  • 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: [email protected].
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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