@article{6e4407f263f044e79d3054c206d54f27,
title = "ASTN2 modultes synaptic strength by trafficking and degradation of surface proteins",
abstract = "Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.",
keywords = "Autism spectrum disorder, Cerebellum, Protein degradation, Protein trafficking, Synapse",
author = "Hourinaz Behesti and Fore, {Taylor R.} and Peter Wu and Zachi Horn and Mary Leppert and Court Hull and Hattena, {Mary E.}",
note = "Funding Information: University); Kunihiro Uryu and Nadine Soplop (Rockefeller University EM Facility); Pablo Ariel and Alison North (Rockefeller University Bio-Imaging); Svetlana Mazel, Selamawit Tadesse, and Stanka Semova (Rockefeller University Flow Cytometry); and Brian Dill (Rockefeller University Proteomics) for expert advice and technical assistance. We thank Drs. Mustafa Sahin (Boston Children{\textquoteright}s Hospital), David Solecki (St. Jude Children{\textquoteright}s Research Hospital), and Eve Govek (The Rockefeller University) for helpful comments on the manuscript and Yin Fang for technical support. We also thank Leila Jamal and Dr. Denise Batista (Kennedy Krieger Institute) for communicating details of patient CNVs and facilitating sample collection. The Neuroligin constructs were kind gifts from Drs. Ann-Marie Craig (University of British Columbia) and Peter Scheiffele (University of Basel), and the SLC12a5 construct was from Dr. Pavel Uvarov (University of Helsinki). This work was supported by the Eugene W. Chinery 2012 Trust (M.E.H.); the Renate, Hans, and Maria Hofmann Trust (H.B. and M.E.H.), NSF Predoctoral Fellowship DGF 1106401 (to T.R.F.), and National Institute of Neurological Disorders and Stroke Grant R01 NS096289-01A1 (to C.H.). The Rockefeller University Proteomics Resource Center acknowledges funding from the Leona M. and Harry B. Helmsley Charitable Trust. This study makes use of data generated by the DECIPHER community; a full list of centers that contributed to the generation of the data is available from https://decipher.sanger.ac.uk/, and funding was provided by the Wellcome Trust. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2018",
month = oct,
day = "9",
doi = "10.1073/pnas.1809382115",
language = "English (US)",
volume = "115",
pages = "E9717--E9726",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "41",
}