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

Martin-de-Saavedra, M. D.; do Santos, M.; Varea, O.; Spielman, B. P.; Gao, R.; Forrest, M.; Myczek, K.; Khalatyan, N.; Hall, E. A.; Sanz-Clemente, A.; Comoletti, D.; Lichtenthaler, S. F.; Savas, J. N.; Penzes, P.

doi:10.1101/605378

bioRxiv · 10.1101/605378

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

Martin-de-Saavedra, M. D.·do Santos, M.·Varea, O.·Spielman, B. P.·Gao, R.·Forrest, M.·Myczek, K.·Khalatyan, N.·Hall, E. A.·Sanz-Clemente, A.·Comoletti, D.·Lichtenthaler, S. F.·Savas, J. N.·Penzes, P.

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Abstract

SUMMARYWhile 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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Martin-de-Saavedra, M. D., do Santos, M., Varea, O., Spielman, B. P., Gao, R., Forrest, M., Myczek, K., Khalatyan, N., Hall, E. A., Sanz-Clemente, A., Comoletti, D., Lichtenthaler, S. F., Savas, J. N., Penzes, P.. 2019-04-10. CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony. https://doi.org/10.1101/605378

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