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CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony

View ORCID ProfileM. Dolores Martin-de-Saavedra, Marc dos Santos, Olga Varea, Benjamin P. Spielman, Ruoqi Gao, View ORCID ProfileMarc Forrest, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, View ORCID ProfileAntonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey N. Savas, View ORCID ProfilePeter Penzes
doi: https://doi.org/10.1101/605378
M. Dolores Martin-de-Saavedra
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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  • ORCID record for M. Dolores Martin-de-Saavedra
Marc dos Santos
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Olga Varea
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Benjamin P. Spielman
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Ruoqi Gao
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Marc Forrest
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Kristoffer Myczek
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Natalia Khalatyan
2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Elizabeth A. Hall
2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Antonio Sanz-Clemente
3Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Davide Comoletti
4School of Biological Sciences, Victoria University of Wellington, 6140, New Zealand
5Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA
6Departments of Neuroscience and Cell Biology, Rutgers, The State University New Jersey, New Brunswick, NJ 08901, USA
7Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University New Jersey, New Brunswick, NJ 08901, USA
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Stefan F. Lichtenthaler
8German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
9Department of Neuroproteomics, School of Medicine, Klinikum rechts der Isar, and Institute for Advanced Study, Technical University of Munich, 81675 Munich, Germany
10Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
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Jeffrey N. Savas
2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Peter Penzes
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
11Northwestern Center for Autism and Neurodevelopment, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
12Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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  • For correspondence: p-penzes@northwestern.edu
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SUMMARY

While many neuronal membrane-anchored proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding. Using mass spectrometry (MS)-based proteomics, we showed that the neuronal sheddome mirrors human cerebrospinal fluid (hCSF). Among shed synaptic proteins in hCSF was the ectodomain of CNTNAP2 (CNTNAP2-ecto), a risk factor for neurodevelopmental disorders (NDD). Using structured-illumination microscopy (SIM), we mapped the spatial organization of neuronal CNTNAP2-ecto shedding. Using affinity chromatography followed by MS, we identified the ATP2B/PMCA Ca2+ extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto coimmunoprecipitates with PMCA2, a known autism risk factor, and enhances its activity, thereby modulating neuronal Ca2+ levels. Finally, we showed that CNTNAP2-ecto regulates neuronal network synchrony in primary cultures and brain slices. These data provide new insights into the biology of synaptic ectodomain shedding and reveal a novel mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony.

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Posted April 10, 2019.
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CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony
M. Dolores Martin-de-Saavedra, Marc dos Santos, Olga Varea, Benjamin P. Spielman, Ruoqi Gao, Marc Forrest, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey N. Savas, Peter Penzes
bioRxiv 605378; doi: https://doi.org/10.1101/605378
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CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony
M. Dolores Martin-de-Saavedra, Marc dos Santos, Olga Varea, Benjamin P. Spielman, Ruoqi Gao, Marc Forrest, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey N. Savas, Peter Penzes
bioRxiv 605378; doi: https://doi.org/10.1101/605378

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