Unraveling VPS13A pathways: from Drosophila to human

Francesco Pinto

    Research output: ThesisThesis fully internal (DIV)

    1328 Downloads (Pure)

    Abstract

    Chorea-Acanthocytosis (ChAc) is a rare human neurodegenerative disease caused by homozygous mutations in the VPS13A gene. Until now no treatment is available and it is not known why mutations in this specific gene lead to neurodegeneration. We established and validated a suitable model organism, Drosophila melanogaster, to study ChAc. Drosophila melanogaster Vps13 mutants showed shortened life span, decreased climbing ability and the presence of vacuoles in the brain. Furthermore, Vps13 mutant flies were sensitive to proteotoxic stress and accumulated ubiquitylated proteins. We performed immunoprecipitation experiments coupled to mass spectrometry (IP-MS) in fly heads using control and Vps13 mutant flies to obtain a list of possible Vps13 interactors and Galectin was identified as a possible candidate. The Interaction between Vps13 and Galectin was validated via immunoprecipitation in cultured insect cells. In addition, we showed that human VPS13A is associated with mitochondria and, through its FFAT domain, interacting with the ER protein VAP-A. These results suggest a role in the formation of ER-mitochondria membrane contact sites. Interestingly, in cells treated with fatty acid, VPS13A translocates from mitochondria to newly synthesized lipid droplets influencing their motility and size. Our data are discussed and reveal an emerging role of VPS13A in preventing neurodegeneration.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Sibon, Ody, Supervisor
    • van Ijzendoorn, Sven, Co-supervisor
    Award date14-Nov-2018
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-1152-1
    Electronic ISBNs978-94-034-1151-4
    Publication statusPublished - 2018

    Fingerprint

    Dive into the research topics of 'Unraveling VPS13A pathways: from Drosophila to human'. Together they form a unique fingerprint.

    Cite this