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    ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington's disease.

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    Name:
    ddab047.pdf
    Size:
    1.604Mb
    Format:
    PDF
    Description:
    Accepted manuscript
    Embargo End Date:
    2022-02-18
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    Type
    Article
    Authors
    Cozzolino, Flora
    Vezzoli, Elena
    Cheroni, Cristina
    Besusso, Dario
    Conforti, Paola
    Valenza, Marta
    Iacobucci, Ilaria
    Monaco, Vittoria
    Birolini, Giulia
    Bombaci, Mauro
    Falqui, Andrea cc
    Saftig, Paul
    Rossi, Riccardo L
    Monti, Maria
    Cattaneo, Elena
    Zuccato, Chiara
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2021-02-18
    Embargo End Date
    2022-02-18
    Permanent link to this record
    http://hdl.handle.net/10754/667515
    
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    Abstract
    Synaptic 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.
    Citation
    OUP accepted manuscript. (2021). Human Molecular Genetics. doi:10.1093/hmg/ddab047
    Sponsors
    We acknowledge the CHDI Foundation for providing zQ175 mice.
    This 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.
    Publisher
    Oxford University Press (OUP)
    Journal
    Human molecular genetics
    DOI
    10.1093/hmg/ddab047
    PubMed ID
    33601422
    Additional Links
    http://fdslive.oup.com/www.oup.com/pdf/production_in_progress.pdf
    ae974a485f413a2113503eed53cd6c53
    10.1093/hmg/ddab047
    Scopus Count
    Collections
    Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program

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