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dc.contributor.authorCozzolino, Flora
dc.contributor.authorVezzoli, Elena
dc.contributor.authorCheroni, Cristina
dc.contributor.authorBesusso, Dario
dc.contributor.authorConforti, Paola
dc.contributor.authorValenza, Marta
dc.contributor.authorIacobucci, Ilaria
dc.contributor.authorMonaco, Vittoria
dc.contributor.authorBirolini, Giulia
dc.contributor.authorBombaci, Mauro
dc.contributor.authorFalqui, Andrea
dc.contributor.authorSaftig, Paul
dc.contributor.authorRossi, Riccardo L
dc.contributor.authorMonti, Maria
dc.contributor.authorCattaneo, Elena
dc.contributor.authorZuccato, Chiara
dc.date.accessioned2021-02-21T07:12:46Z
dc.date.available2021-02-21T07:12:46Z
dc.date.issued2021-02-18
dc.identifier.citationOUP accepted manuscript. (2021). Human Molecular Genetics. doi:10.1093/hmg/ddab047
dc.identifier.issn0964-6906
dc.identifier.pmid33601422
dc.identifier.doi10.1093/hmg/ddab047
dc.identifier.urihttp://hdl.handle.net/10754/667515
dc.description.abstractSynaptic dysfunction and cognitive decline in Huntington's disease (HD) involve hyperactive A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed an immunoaffinity purification-mass spectrometry (IP-MS) study of endogenous ADAM10 in the brains of wild-type and HD mice. In the normal brain, proteins implicated in synapse organization, synaptic plasticity, and vesicle and organelles trafficking interact with ADAM10, suggesting that it may act as a hub protein at the excitatory synapse. Importantly, the ADAM10 interactome is enriched in presynaptic proteins and ADAM10 coimmunoprecipitates with piccolo (PCLO), a key player in the recycling and maintenance of synaptic vesicles (SVs). In contrast, reduced ADAM10/PCLO immunoprecipitation occurs in the HD brain, with decreased density of SVs in the reserve and docked pool at the HD presynaptic terminal. Conditional heterozygous deletion of ADAM10 in the forebrain of HD mice reduces active ADAM10 to wild-type level, and normalizes ADAM10/PCLO complex formation and SVs density and distribution. The results indicate that presynaptic ADAM10 and PCLO are a relevant component of HD pathogenesis.
dc.description.sponsorshipWe acknowledge the CHDI Foundation for providing zQ175 mice.
dc.description.sponsorshipThis study was supported by Telethon (GGP13053) to CZ, Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (20128XWKTX) to CZ and MM, ModelPolyQ (JPCOFUND-643417) and CircProt (JPCOFUND-643417) to EC, Deutsche Forschungsgemeinschaft (DFG-SFB877-A3) to PS, and KAUST baseline funding to AF.
dc.publisherOxford University Press (OUP)
dc.relation.urlhttp://fdslive.oup.com/www.oup.com/pdf/production_in_progress.pdf
dc.rightsThis is a pre-copyedited, author-produced PDF of an article accepted for publication in Human molecular genetics following peer review. The version of record is available online at: http://fdslive.oup.com/www.oup.com/pdf/production_in_progress.pdf.
dc.titleADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington's disease.
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.identifier.journalHuman molecular genetics
dc.rights.embargodate2022-02-18
dc.eprint.versionPost-print
dc.contributor.institutionDepartment of Chemical Sciences, University of Naples
dc.contributor.institutionCEINGE Advanced Biotechnologies, 80131 Naples, Italy.
dc.contributor.institutionDepartment of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy.
dc.contributor.institutionEuropean Institute of Oncology, IRCCS, 20141 Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, 20122 Milan, Italy.
dc.contributor.institutionDepartment of Biosciences, University of Milan, 20133 Milan, Italy.
dc.contributor.institutionIstituto Nazionale di Genetica Molecolare
dc.contributor.institutionBiostructures and Biosystems National Institute (INBB), 00136 Rome, Italy.
dc.contributor.institutionInstitute of Biochemistry, Christian-Albrechts-University of Kiel, D-24098 Kiel, Germany.
kaust.personFalqui, Andrea
refterms.dateFOA2021-02-21T07:14:52Z
kaust.acknowledged.supportUnitBaseline funding


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