TY  - JOUR
AU  - Kumar, Manoj
AU  - Srikanth, Manasa P
AU  - Deleidi, Michela
AU  - Hallett, Penelope J
AU  - Isacson, Ole
AU  - Feldman, Ricardo A
TI  - Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.
JO  - Human molecular genetics
VL  - 32
IS  - 11
SN  - 0964-6906
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2023-00558
SP  - 1888 - 1900
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Parkinson Disease: metabolism
KW  - alpha-Synuclein: genetics
KW  - alpha-Synuclein: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - MTOR Inhibitors
KW  - Acid Ceramidase: genetics
KW  - Acid Ceramidase: metabolism
KW  - Glucosylceramidase: genetics
KW  - Glucosylceramidase: metabolism
KW  - Gaucher Disease: metabolism
KW  - Dopaminergic Neurons: metabolism
KW  - TOR Serine-Threonine Kinases: genetics
KW  - Mechanistic Target of Rapamycin Complex 1: genetics
KW  - Mutation
KW  - Lysosomes: metabolism
KW  - alpha-Synuclein (NLM Chemicals)
KW  - MTOR Inhibitors (NLM Chemicals)
KW  - Acid Ceramidase (NLM Chemicals)
KW  - Glucosylceramidase (NLM Chemicals)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
KW  - Mechanistic Target of Rapamycin Complex 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36752535
C2  - pmc:PMC10196677
DO  - DOI:10.1093/hmg/ddad025
UR  - https://pub.dzne.de/record/258096
ER  -