The epilepsy-associated protein PCDH19 undergoes NMDA receptor-dependent proteolytic cleavage and regulates the expression of immediate-early genes
Articolo
Data di Pubblicazione:
2022
Citazione:
The epilepsy-associated protein PCDH19 undergoes NMDA receptor-dependent proteolytic cleavage and regulates the expression of immediate-early genes / L. Gerosa, S. Mazzoleni, F. Rusconi, A. Longaretti, E. Lewerissa, S. Pelucchi, L. Murru, S.G. Giannelli, V. Broccoli, E. Marcello, N.N. Kasri, E. Battaglioli, M. Passafaro, S. Bassani. - In: CELL REPORTS. - ISSN 2211-1247. - 39:8(2022 May 24), pp. 110857.1-110857.14.e1-e7. [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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
CP: Microbiology; CP: Neuroscience; DEE9; LSD1; PCDH19; immediate-early genes; neurodevelopmental disorders; proteolytic cleavage; protocadherin; synapse; Chromatin; Gene Expression Regulation; Humans; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Cadherins; Epilepsy; Genes, Immediate-Early; Protocadherins
Elenco autori:
L. Gerosa, S. Mazzoleni, F. Rusconi, A. Longaretti, E. Lewerissa, S. Pelucchi, L. Murru, S.G. Giannelli, V. Broccoli, E. Marcello, N.N. Kasri, E. Battaglioli, M. Passafaro, S. Bassani
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