title: A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.
abstract: Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Beavan
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Kai-Yin
authors.initials: KY
authors.lastname: Chau
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK. Electronic address: a.schapira@ucl.ac.uk.
authors.forename: Anthony H V
authors.initials: AHV
authors.lastname: Schapira
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000551:Ambroxol / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002454:Cell Differentiation; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D052119:Lysosomal-Associated Membrane Protein 2; D051844:alpha-Synuclein; D000551:Ambroxol; D005962:Glucosylceramidase
keywords: GBA1 mutation; GBA1-associated PD; PD modeling; Parkinson disease; ambroxol; chaperone; dopaminergic neurons; glucocerebrosidase; neural crest stem cells; α-synuclein