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; Hiba A. Jalloul; Kristoffer Myczek; Natalia Khalatyan; Elizabeth A. Hall; Liam S. Turk; Antonio Sanz-Clemente; Davide Comoletti; Stefan F. Lichtenthaler; Jeffrey S. Burgdorf; Maria V. Barbolina; Jeffrey N. Savas; Peter Penzes

doi:10.1016/j.neuron.2021.11.025

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, Hiba A. Jalloul, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Liam S. Turk, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey S. Burgdorf, Maria V. BarbolinaJeffrey N. Savas, Peter Penzes

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	627-643.e9
Journal	Neuron
Volume	110
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2021.11.025
State	Published - 16 Feb 2022
Externally published	Yes

Keywords

CNTNAP2
autism
bioinformatics
calcium
cerebrospinal fluid
ectodomain shedding
network dynamics
proteomics
schizophrenia
sheddome

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10.1016/j.neuron.2021.11.025

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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

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

abstract = "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.",

keywords = "CNTNAP2, autism, bioinformatics, calcium, cerebrospinal fluid, ectodomain shedding, network dynamics, proteomics, schizophrenia, sheddome",

author = "Mart{\'i}n-de-Saavedra, {M. Dolores} and {Dos Santos}, Marc and Lorenza Culotta and Olga Varea and Spielman, {Benjamin P.} and Euan Parnell and Forrest, {Marc P.} and Ruoqi Gao and Sehyoun Yoon and Emmarose McCoig and Jalloul, {Hiba A.} and Kristoffer Myczek and Natalia Khalatyan and Hall, {Elizabeth A.} and Turk, {Liam S.} and Antonio Sanz-Clemente and Davide Comoletti and Lichtenthaler, {Stefan F.} and Burgdorf, {Jeffrey S.} and Barbolina, {Maria V.} and Savas, {Jeffrey N.} and Peter Penzes",

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year = "2022",

month = feb,

day = "16",

doi = "10.1016/j.neuron.2021.11.025",

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Martín-de-Saavedra, MD, Dos Santos, M, Culotta, L, Varea, O, Spielman, BP, Parnell, E, Forrest, MP, Gao, R, Yoon, S, McCoig, E, Jalloul, HA, Myczek, K, Khalatyan, N, Hall, EA, Turk, LS, Sanz-Clemente, A, Comoletti, D, Lichtenthaler, SF, Burgdorf, JS, Barbolina, MV, Savas, JN & Penzes, P 2022, 'Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca²⁺ homeostasis and network synchrony via PMCA2/ATP2B2', Neuron, vol. 110, no. 4, pp. 627-643.e9. https://doi.org/10.1016/j.neuron.2021.11.025

TY - JOUR

T1 - Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2

AU - Martín-de-Saavedra, M. Dolores

AU - Dos Santos, Marc

AU - Culotta, Lorenza

AU - Varea, Olga

AU - Spielman, Benjamin P.

AU - Parnell, Euan

AU - Forrest, Marc P.

AU - Gao, Ruoqi

AU - Yoon, Sehyoun

AU - McCoig, Emmarose

AU - Jalloul, Hiba A.

AU - Myczek, Kristoffer

AU - Khalatyan, Natalia

AU - Hall, Elizabeth A.

AU - Turk, Liam S.

AU - Sanz-Clemente, Antonio

AU - Comoletti, Davide

AU - Lichtenthaler, Stefan F.

AU - Burgdorf, Jeffrey S.

AU - Barbolina, Maria V.

AU - Savas, Jeffrey N.

AU - Penzes, Peter

PY - 2022/2/16

Y1 - 2022/2/16

N2 - 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.

AB - 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.

KW - CNTNAP2

KW - autism

KW - bioinformatics

KW - calcium

KW - cerebrospinal fluid

KW - ectodomain shedding

KW - network dynamics

KW - proteomics

KW - schizophrenia

KW - sheddome

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U2 - 10.1016/j.neuron.2021.11.025

DO - 10.1016/j.neuron.2021.11.025

M3 - Article

C2 - 34921780

AN - SCOPUS:85122931489

SN - 0896-6273

VL - 110

SP - 627-643.e9

JO - Neuron

JF - Neuron

IS - 4

ER -

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

Abstract

Keywords

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