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Intersectin Associates with Synapsin and Regulates Its Nanoscale Localization and Function

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Intersectin Associates with Synapsin and Regulates Its Nanoscale Localization and Function Correction NEUROSCIENCE Correction for “Intersectin associates with synapsin and regu- lates its nanoscale localization and function,” by Fabian Gerth, Maria Jäpel, Arndt Pechstein, Gaga Kochlamazashvili, Martin Lehmann, Dmytro Puchkov, Franco Onofri, Fabio Benfenati, Alexander G. Nikonenko, Tanja Maritzen, Christian Freund, and Volker Haucke, which was first published October 23, 2017; 10.1073/pnas.1715341114 (Proc Natl Acad Sci USA 114:12057– 12062). The authors note that Kristin Fredrich and Oleg Shupliakov should be added to the author list as the 10th and 11th authors, re- spectively, between Alexander G. Nikonenko and Tanja Maritzen. KristinFredrichshouldbecreditedwithcontributingnewreagents/ analytic tools, and Oleg Shupliakov should be credited with de- signing research. The corrected author line, affiliation line, and author contributions appear below. The author information in the online version has been corrected. The authors also note that the following statements should be added to the Acknowledgments: “This work was also supported by Swedish Research Council Grants VRM N01501 and RSF N16-15-10273 (to O.S.). A.P. received a post-doctoral fellowship from the Swedish Research Council, Grant N21627.” Fabian Gertha, Maria Jäpelb, Arndt Pechsteina,b, Gaga Kochlamazashvilib, Martin Lehmannb, Dmytro Puchkovb, Franco Onofric, Fabio Benfenatic,d, Alexander G. Nikonenkoe, Kristin Fredrichf, Oleg Shupliakovf,g, Tanja Maritzenb, Christian Freunda, and Volker Hauckea,b aFaculty of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; bDepartment of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; cDepartment of Experimental Medicine, University of Genoa, 16132 Genoa, Italy; dCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; eDepartment of Cytology, Bogomoletz Institute of Physiology, 01024 Kiev, Ukraine; fDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; and gInstitute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia Author contributions: A.P., G.K., M.L., D.P., F.B., O.S., C.F., and V.H. designed research; F.G., M.J., A.P., G.K., D.P., and F.O. performed research; F.G., M.J., A.P., M.L., F.O., F.B., A.G.N., K.F., T.M., and C.F. contributed new reagents/ analytic tools; F.G., M.J., A.P., G.K., M.L., D.P., C.F., and V.H. analyzed data; and C.F. and V.H. wrote the paper. Published under the PNAS license. www.pnas.org/cgi/doi/10.1073/pnas.1720226115 E11060 | PNAS | December 19, 2017 | vol. 114 | no. 51 www.pnas.org Downloaded by guest on September 29, 2021 Intersectin associates with synapsin and regulates its nanoscale localization and function Fabian Gertha,1, Maria Jäpelb,1, Arndt Pechsteina,b,1, Gaga Kochlamazashvilib, Martin Lehmannb, Dmytro Puchkovb, Franco Onofric, Fabio Benfenatic,d, Alexander G. Nikonenkoe, Kristin Fredrichf, Oleg Shupliakovf,g, Tanja Maritzenb, Christian Freunda,2, and Volker Hauckea,b,2 aFaculty of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; bDepartment of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; cDepartment of Experimental Medicine, University of Genoa, 16132 Genoa, Italy; dCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; eDepartment of Cytology, Bogomoletz Institute of Physiology, 01024 Kiev, Ukraine; fDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; and gInstitute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia Edited by Pietro De Camilli, Howard Hughes Medical Institute, Yale University, New Haven, CT, and approved September 28, 2017 (received for review September 1, 2017) Neurotransmission is mediated by the exocytic release of neuro- have been suggested to regulate actin dynamics and to couple the transmitters from readily releasable synaptic vesicles (SVs) at the exo/endocytic limbs of the SV cycle (14). Intersectin 1 deletion in active zone. To sustain neurotransmission during periods of elevated mice causes a comparably mild presynaptic phenotype (15, 16), activity, release-ready vesicles need to be replenished from the while its overexpression is associatedwithDownsyndromeinhu- reserve pool of SVs. The SV-associated synapsins are crucial for mans (17). Loss of Dap160, the Drosophila melanogaster homolog maintaining this reserve pool and regulate the mobilization of of mammalian intersectins, has been linked to defects in neuro- reserve pool SVs. How replenishment of release-ready SVs from transmission, SV cycling, and SV pool organization (18, 19), sug- the reserve pool is regulated and which other factors cooperate with gesting that intersectins serve as multifunctional scaffolds that synapsins in this process is unknown. Here we identify the endocytic coordinate different steps in the SV cycle (14). How these diverse multidomain scaffold protein intersectin as an important regulator of functions of intersectin are controlled in molecular terms is SV replenishment at hippocampal synapses. We found that inter- unknown. sectin directly associates with synapsin I through its Src-homology 3 Here we combine mouse genetics, superresolution imaging, A domain, and this association is regulated by an intramolecular electrophysiology, and NMR-based structural studies to identify switch within intersectin 1. Deletion of intersectin 1/2 in mice alters a key role for intersectin in SV replenishment at hippocampal the presynaptic nanoscale distribution of synapsin I and causes synapses by regulated complex formation with synapsin I. defects in sustained neurotransmission due to defective SV replen- Results ishment. These phenotypes were rescued by wild-type intersectin 1 Intersectin Associates with Synapsin I in Central Synapses. but not by a locked mutant of intersectin 1. Our data reveal The mo- intersectin as an autoinhibited scaffold that serves as a molecular lecular basis for the enrichment of endocytic proteins in nerve linker between the synapsin-dependent reserve pool and the pre- terminals (13) is unknown. Hence, we screened for possible inter- actions between known presynaptic components and the endocytic synaptic endocytosis machinery. neurotransmission | synaptic vesicles | multidomain scaffold | Significance intramolecular regulation | NMR spectroscopy Mutations in genes regulating neurotransmission in the brain eurotransmission is based on the fusion of readily releasable are implicated in neurological disorders and neurodegeneration. Nsynaptic vesicles (SVs) at the presynaptic active zone (1, 2). Synapsin is a crucial regulator of neurotransmission and allows NEUROSCIENCE Fusing SVs are concomitantly replenished by compensatory en- synapses to maintain a large reserve pool of synaptic vesicles. docytosis of SV membranes and clathrin-mediated reformation Human mutations in synapsin genes are linked to epilepsy of SVs (3, 4). During sustained periods of activity the recycling and autism. How synapsin function is regulated to allow re- plenishment of synaptic vesicles and sustain neurotransmission vesicle pool is refilled by mobilization of SVs from the reserve is largely unknown. Here we identify a function for the endo- pool (5). The synapsins (synapsin I, II, and III), are major cytic scaffold protein intersectin, a protein overexpressed in SV-associated phosphoproteins encoded by three distinct genes patients with Down syndrome, as a regulator of synapsin that are required for the formation and maintenance of the re- nanoscale distribution and function that is controlled by a serve/recycling pools of SVs via association with the actin cyto- – phosphorylation-dependent autoinhibitory switch. Our results skeleton (6 8). Activity-dependent phosphorylation of synapsin I unravel a hitherto unknown molecular connection between by several kinases at distinct sites regulates its association with the machineries for synaptic vesicle reserve pool organization SV membranes and F-actin to control SV mobilization from the and endocytosis. reserve pool (6). Consistently, loss of synapsin I causes depletion of reserve pool SVs and a marked impairment in inhibitory Author contributions: A.P., G.K., M.L., D.P., F.B., O.S., C.F., and V.H. designed research; transmission (9, 10), resulting in an epileptic and autistic phe- F.G., M.J., A.P., G.K., D.P., and F.O. performed research; F.G., M.J., A.P., M.L., F.O., F.B., notype in mice (8, 11) and humans (12). A.G.N., K.F., T.M., and C.F. contributed new reagents/analytic tools; F.G., M.J., A.P., G.K., Endocytic proteins are enriched within the presynaptic com- M.L., D.P., C.F., and V.H. analyzed data; and C.F. and V.H. wrote the paper. partment at steady state (13). Upon synaptic activity they are The authors declare no conflict of interest. recruitedtotheso-called“periactive zone” that surrounds active This article is a PNAS Direct Submission. zone (AZ) release sites to facilitate endocytic membrane in- This is an open access article distributed under the PNAS license. ternalization and SV reformation. Among the endocytic proteins 1F.G., M.J., and A.P. contributed equally to this work. shown to undergo activity-dependent movement to the periactive 2To whom correspondence may be addressed. Email: [email protected] or zone are intersectin 1 and 2, large scaffolds containing five Src
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