@article{0d11c61d2e7748808fb85f4f154e5f66,
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",
note = "Funding Information: This work was supported by grant MH097216 from the US National Institute of Mental Health (to P.P.), by an individual Biomedical Research Award from the Martwell Foundation (to J.N.S), by the National Institutes of Health (NIH) grant R01-MH092906 (to D.C.), by the New Jersey Commission on Traumatic Brain Injury Research (CBIR16PIL035 to D.C.), and from the Fred & Santa Barile Children's Medical Research Trust (to D.C.). SIM imaging work was performed at the Northwestern University Center for Advanced Microscopy, generously supported by National Cancer Institute grant CCSG-P30-CA060553. The Nikon N-SIM system was purchased through the support of NIH grant 1S10OD016342-01. We thank Drs. Constadina Arvanitis and David Kirchenb{\"u}chler for help with SIM imaging and live Ca2+ imaging. hCSF was obtained from the NIH Neurobiobank at the University of Maryland, Baltimore (MD). M.D.M.S. M.D.S. L.C. O.V. B.P.S. R.G. S.Y. M.P.F. E.M. H.A.J. K.M. N.K. E.A.H. L.S.T. A.S.C. J.S.B. M.V.B. and D.C. conducted experiments; P.P. M.D.M.S. M.D.S. O.V. and J.N.S. designed experiments; M.D.M.S. M.D.S. L.C. E.P. P.P. M.V.B. S.F.L. and J.N.S. analyzed the data; P.P. and M.D.M.S. conceptualized the research and wrote the paper. The authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects.We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper received support from a program designed to increase minority representation in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: This work was supported by grant MH097216 from the US National Institute of Mental Health (to P.P.), by an individual Biomedical Research Award from the Martwell Foundation (to J.N.S), by the National Institutes of Health (NIH) grant R01-MH092906 (to D.C.), by the New Jersey Commission on Traumatic Brain Injury Research ( CBIR16PIL035 to D.C.), and from the Fred & Santa Barile Children{\textquoteright}s Medical Research Trust (to D.C.). SIM imaging work was performed at the Northwestern University Center for Advanced Microscopy, generously supported by National Cancer Institute grant CCSG-P30-CA060553 . The Nikon N-SIM system was purchased through the support of NIH grant 1S10OD016342-01 . We thank Drs. Constadina Arvanitis and David Kirchenb{\"u}chler for help with SIM imaging and live Ca 2+ imaging. hCSF was obtained from the NIH Neurobiobank at the University of Maryland, Baltimore (MD). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = feb,
day = "16",
doi = "10.1016/j.neuron.2021.11.025",
language = "English (US)",
volume = "110",
pages = "627--643.e9",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}