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@ARTICLE{Kumar:258096,
      author       = {Kumar, Manoj and Srikanth, Manasa P and Deleidi, Michela
                      and Hallett, Penelope J and Isacson, Ole and Feldman,
                      Ricardo A},
      title        = {{A}cid ceramidase involved in pathogenic cascade leading to
                      accumulation of α-synuclein in i{PSC} model of
                      {GBA}1-associated {P}arkinson's disease.},
      journal      = {Human molecular genetics},
      volume       = {32},
      number       = {11},
      issn         = {0964-6906},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2023-00558},
      pages        = {1888 - 1900},
      year         = {2023},
      abstract     = {Bi-allelic mutations in GBA1, the gene that encodes
                      β-glucocerebrosidase (GCase), cause Gaucher disease (GD),
                      whereas mono-allelic mutations do not cause overt pathology.
                      Yet mono- or bi-allelic GBA1 mutations are the highest known
                      risk factor for Parkinson's disease (PD). GCase deficiency
                      results in the accumulation of glucosylceramide (GluCer) and
                      its deacylated metabolite glucosylsphingosine (GluSph).
                      Brains from patients with neuronopathic GD have high levels
                      of GluSph, and elevation of this lipid in GBA1-associated PD
                      has been reported. To uncover the mechanisms involved in
                      GBA1-associated PD, we used human induced pluripotent stem
                      cell-derived dopaminergic (DA) neurons from patients
                      harboring heterozygote mutations in GBA1 (GBA1/PD-DA
                      neurons). We found that compared with gene-edited isogenic
                      controls, GBA1/PD-DA neurons exhibit mammalian target of
                      rapamycin complex 1 (mTORC1) hyperactivity, a block in
                      autophagy, an increase in the levels of phosphorylated
                      α-synuclein (129) and α-synuclein aggregation. These
                      alterations were prevented by incubation with mTOR
                      inhibitors. Inhibition of acid ceramidase, the lysosomal
                      enzyme that deacylates GluCer to GluSph, prevented mTOR
                      hyperactivity, restored autophagic flux and lowered
                      α-synuclein levels, suggesting that GluSph was responsible
                      for these alterations. Incubation of gene-edited wild type
                      (WT) controls with exogenous GluSph recapitulated the
                      mTOR/α-synuclein abnormalities of GBA1/PD neurons, and
                      these phenotypic alterations were prevented when GluSph
                      treatment was in the presence of mTOR inhibitors. We
                      conclude that GluSph causes an aberrant activation of
                      mTORC1, suppressing normal lysosomal functions, including
                      the clearance of pathogenic α-synuclein species. Our
                      results implicate acid ceramidase in the pathogenesis of
                      GBA1-associated PD, suggesting that this enzyme is a
                      potential therapeutic target for treating synucleinopathies
                      caused by GCase deficiency.},
      keywords     = {Humans / Parkinson Disease: metabolism / alpha-Synuclein:
                      genetics / alpha-Synuclein: metabolism / Induced Pluripotent
                      Stem Cells: metabolism / MTOR Inhibitors / Acid Ceramidase:
                      genetics / Acid Ceramidase: metabolism / Glucosylceramidase:
                      genetics / Glucosylceramidase: metabolism / Gaucher Disease:
                      metabolism / Dopaminergic Neurons: metabolism / TOR
                      Serine-Threonine Kinases: genetics / Mechanistic Target of
                      Rapamycin Complex 1: genetics / Mutation / Lysosomes:
                      metabolism / alpha-Synuclein (NLM Chemicals) / MTOR
                      Inhibitors (NLM Chemicals) / Acid Ceramidase (NLM Chemicals)
                      / Glucosylceramidase (NLM Chemicals) / TOR Serine-Threonine
                      Kinases (NLM Chemicals) / Mechanistic Target of Rapamycin
                      Complex 1 (NLM Chemicals)},
      cin          = {AG Deleidi},
      ddc          = {570},
      cid          = {I:(DE-2719)1210011},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36752535},
      pmc          = {pmc:PMC10196677},
      doi          = {10.1093/hmg/ddad025},
      url          = {https://pub.dzne.de/record/258096},
}