ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington's disease.
Type
ArticleAuthors
Cozzolino, FloraVezzoli, Elena
Cheroni, Cristina
Besusso, Dario
Conforti, Paola
Valenza, Marta
Iacobucci, Ilaria
Monaco, Vittoria
Birolini, Giulia
Bombaci, Mauro
Falqui, Andrea

Saftig, Paul
Rossi, Riccardo L
Monti, Maria
Cattaneo, Elena
Zuccato, Chiara
KAUST Department
Biological and Environmental Science and Engineering (BESE) DivisionBioscience Program
Date
2021-02-18Online Publication Date
2021-02-18Print Publication Date
2021-06-17Embargo End Date
2022-02-18Permanent link to this record
http://hdl.handle.net/10754/667515
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Show full item recordAbstract
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/ddab047Sponsors
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 geneticsPubMed ID
33601422Additional Links
http://fdslive.oup.com/www.oup.com/pdf/production_in_progress.pdfae974a485f413a2113503eed53cd6c53
10.1093/hmg/ddab047
Scopus Count
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