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    mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells

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    Author
    Brown, R.A.
    Voit, A.
    Srikanth, M.P.
    Thayer, J.A.
    Kingsbury, T.J.
    Lipinski, M.M.
    Feldman, R.A.
    Awad, O.
    Date
    2019
    Journal
    Disease models & mechanisms
    Publisher
    The Company of Biologists
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1242/dmm.038596
    Abstract
    Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. GBA1 mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in GBA1-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). To further investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD, we examined mTORC1 kinase activity in GD iPSC neuronal progenitors and differentiated neurons. We found that mTORC1 is hyperactive in GD cells as evidenced by increased phosphorylation of its downstream protein substrates. We also found that pharmacological inhibition of glucosylceramide synthase enzyme reversed mTORC1 hyperactivation, suggesting that increased mTORC1 activity is mediated by the abnormal accumulation of glycosphingolipids in the mutant cells. Treatment with the mTOR inhibitor Torin1 upregulated lysosomal biogenesis and enhanced autophagic clearance in GD neurons, confirming that lysosomal dysfunction is mediated by mTOR hyperactivation. Further analysis demonstrated that increased TFEB phosphorylation by mTORC1 results in decreased TFEB stability in GD cells. Our study uncovers a new mechanism contributing to autophagy-lysosomal pathway dysfunction in GD, and identifies the mTOR complex as a potential therapeutic target for treatment of GBA1-associated neurodegeneration.
    Keyword
    GBA1 mutations
    iPSC
    Lysosomal storage disorder
    mTORC1
    TFEB
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85073665222&doi=10.1242%2fdmm.038596&partnerID=40&md5=dcc83af4be41753cb374f1019830f2d6; http://hdl.handle.net/10713/11235
    ae974a485f413a2113503eed53cd6c53
    10.1242/dmm.038596
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