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Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2
Journal article   Open access   Peer reviewed

Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2

M. Dolores Martín-de-Saavedra, Marc Dos Santos, Lorenza Culotta, Olga Varea, Benjamin P. Spielman, Euan Parnell, Marc P. Forrest, Ruoqi Gao, Sehyoun Yoon, Emmarose McCoig, …
Neuron (Cambridge, Mass.), v 110(4), pp 627-643
16 Feb 2022
DOI: https://doi.org/10.1016/j.neuron.2021.11.025
PMID: 34921780
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1016/j.neuron.2021.11.025View
Published, Version of Record (VoR)Open Access (Publisher-Specific),  Open

Abstract

autism bioinformatics calcium cerebrospinal fluid CNTNAP2 ectodomain shedding network dynamics proteomics schizophrenia sheddome
Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and is enriched in neurodevelopmental disorder (NDD) risk factors. Among shed synaptic proteins is the ectodomain of CNTNAP2 (CNTNAP2-ecto), a prominent NDD risk factor. CNTNAP2 undergoes activity-dependent ES via MMP9 (matrix metalloprotease 9), and CNTNAP2-ecto levels are reduced in the hCSF of individuals with autism spectrum disorder. Using mass spectrometry, we identified the plasma membrane Ca2+ ATPase (PMCA) extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto enhances the activity of PMCA2 and regulates neuronal network dynamics in a PMCA2-dependent manner. Our data underscore the promise of sheddome analysis in discovering neurobiological mechanisms, provide insight into the biology of ES and its relationship with the CSF, and reveal a mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony by a shed ectodomain. •The neuronal sheddome is enriched in neurodevelopmental disorder risk factors•CNTNAP2 is cleaved, and its ectodomain is detectable in the cerebrospinal fluid•Neuron activity boosts CNTNAP2 shedding and the ectodomain binds to Ca2+ pump PMCA2•CNTNAP2 ectodomain enhances Ca2+ extrusion and reduces neuronal network synchrony Martin-de-Saavedra et al. report that the neuronal sheddome is detectable in human cerebrospinal fluid and is enriched in neurodevelopmental disorder risk factors. Among them is the CNTNAP2 ectodomain. Its synaptic shedding is increased by neuronal activity. CNTNAP2-ecto binds and activates PMCA Ca2+ extrusion pumps and thereby decreases neuronal network synchrony.

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Neurosciences
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