Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1

Maria K Lehtinen, Saara Tegelberg, Hyman Schipper, Haixiang Su, Hillel Zukor, Otto Manninen, Outi Kopra, Tarja Hannele Joensuu, Paula Hakala, Azad Bonni, Anna-Elina Lehesjoki

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

    Abstrakti

    The progressive myoclonus epilepsies, featuring the triad of myoclonus, seizures, and ataxia, comprise a large group of inherited neurodegenerative diseases that remain poorly understood and refractory to treatment. The Cystatin B gene is mutated in one of the most common forms of progressive myoclonus epilepsy, Unverricht-Lundborg disease (EPM1). Cystatin B knockout in a mouse model of EPM1 triggers progressive degeneration of cerebellar granule neurons. Here, we report impaired redox homeostasis as a key mechanism by which Cystatin B deficiency triggers neurodegeneration. Oxidative stress induces the expression of Cystatin B in cerebellar granule neurons, and EPM1 patient-linked mutation of the Cystatin B gene promoter impairs oxidative stress induction of Cystatin B transcription. Importantly, Cystatin B knockout or knockdown sensitizes cerebellar granule neurons to oxidative stress-induced cell death. The Cystatin B deficiency-induced predisposition to oxidative stress in neurons is mediated by the lysosomal protease Cathepsin B. We uncover evidence of oxidative damage, reflected by depletion of antioxidants and increased lipid peroxidation, in the cerebellum of Cystatin B knock-out mice in vivo. Collectively, our findings define a pathophysiological mechanism in EPM1, whereby Cystatin B deficiency couples oxidative stress to neuronal death and degeneration, and may thus provide the basis for novel treatment approaches for the progressive myoclonus epilepsies.
    Alkuperäiskielienglanti
    LehtiJournal of Neuroscience
    Vuosikerta29
    Numero18
    Sivut5910-5915
    Sivumäärä6
    ISSN0270-6474
    DOI - pysyväislinkit
    TilaJulkaistu - 2009
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

    Tieteenalat

    • 311 Peruslääketieteet
    • 118 Biotieteet
    • 515 Psykologia

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