21 Martin-de-Saavedra Neuron.pdf (4.85 MB)
Download file

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

Download (4.85 MB)
journal contribution
posted on 04.08.2022, 05:42 authored by MD Martín-de-Saavedra, M Dos Santos, L Culotta, O Varea, BP Spielman, E Parnell, MP Forrest, R Gao, S Yoon, E McCoig, HA Jalloul, K Myczek, N Khalatyan, EA Hall, LS Turk, A Sanz-Clemente, Davide ComolettiDavide Comoletti, SF Lichtenthaler, JS Burgdorf, MV Barbolina, JN Savas, P Penzes
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.

History

Preferred citation

Martín-de-Saavedra, M. D., Dos Santos, M., Culotta, L., Varea, O., Spielman, B. P., Parnell, E., Forrest, M. P., Gao, R., Yoon, S., McCoig, E., Jalloul, H. A., Myczek, K., Khalatyan, N., Hall, E. A., Turk, L. S., Sanz-Clemente, A., Comoletti, D., Lichtenthaler, S. F., Burgdorf, J. S.,... Penzes, P. (2022). Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2. Neuron, 110(4), 627-643.e9. https://doi.org/10.1016/j.neuron.2021.11.025

Journal title

Neuron

Volume

110

Issue

4

Publication date

16/02/2022

Pagination

627-643.e9

Publisher

Elsevier BV

Publication status

Published

Online publication date

01/02/2022

ISSN

0896-6273

eISSN

1097-4199

Language

en