Principal Investigators

    Dr. D.S. Verbeek


    University Medical Center Groningen

    Contact information of lead PI



    Title of project or programme

    Towards the understanding of pathological protein processing and toxicity in Machado-Joseph disease.

    Source of funding information


    Total sum awarded (Euro)

    € 134,900

    Start date of award


    Total duration of award in years



    Research Abstract

    Machado-Joseph Disease (MJD, syn. spinocerebellar ataxia type 3; SCA3) is an autosomal dominantly inherited
    neurodegenerative disorder caused by expansion of polyglutamine(polyQ)-encoding CAG repeats in the MJD1 gene. Neuronal
    nuclear inclusions (NNI)containing the gene product ataxin-3 (ATXN3) are a hallmark of MJD. Compelling evidence indicates
    that the proteolytic cleavage of ATXN3 leads to the formation of misfolded intermediates, which eventually accumulate to form
    NNIs. However, the exact mechanism of how mutated ATXN3 is processed in the cell, how this mostly cytoplasmatic protein is
    shuffled to the nucleus, which other genetic predisposition factors determine disease severity and the exact relationship
    ATXN3 aggregation and toxicity remains elusive. We will combine latest cell culture techniques with state-of-the-art biochemical
    studies,neurogenetics, imaging and animal models. Specifically, we will identify candidates of genetic modifiers by deep
    sequencing in a cohort of MJD patients. Special emphasis in our studies will lie on the subcellular localization of ATXN3 related
    to toxicity and the autophagy degradation pathway. Induced pluripotent stem cells (iPSC) will serve as a new in vitro model to
    study cleavage, aggregation, processing, stress and toxicity directly in human neurons. Applying high-resolution live-cell imaging will facilitate real-time assessment of aggregation and proteotoxicity. We expect this consortium to generate fundamental new insight into the pathology of MJD in a highly innovative and complementary fashion.

    Further information available at:

Types: Investments < €500k
Member States: Netherlands
Diseases: N/A
Years: 2016
Database Categories: N/A
Database Tags: N/A

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