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| Home > Publications Database > Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease. > print |
| Home > Publications Database > Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease. > print |
| 001 | 258096 | ||
| 005 | 20231120155345.0 | ||
| 024 | 7 | _ | |a 10.1093/hmg/ddad025 |2 doi |
| 024 | 7 | _ | |a pmid:36752535 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC10196677 |2 pmc |
| 024 | 7 | _ | |a 0964-6906 |2 ISSN |
| 024 | 7 | _ | |a 1460-2083 |2 ISSN |
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| 037 | _ | _ | |a DZNE-2023-00558 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Kumar, Manoj |b 0 |
| 245 | _ | _ | |a Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease. |
| 260 | _ | _ | |a Oxford |c 2023 |b Oxford Univ. Press |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1686040335_28874 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 352 - Disease Mechanisms (POF4-352) |0 G:(DE-HGF)POF4-352 |c POF4-352 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de |
| 650 | _ | 7 | |a alpha-Synuclein |2 NLM Chemicals |
| 650 | _ | 7 | |a MTOR Inhibitors |2 NLM Chemicals |
| 650 | _ | 7 | |a Acid Ceramidase |0 EC 3.5.1.23 |2 NLM Chemicals |
| 650 | _ | 7 | |a Glucosylceramidase |0 EC 3.2.1.45 |2 NLM Chemicals |
| 650 | _ | 7 | |a TOR Serine-Threonine Kinases |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a Mechanistic Target of Rapamycin Complex 1 |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: genetics |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: metabolism |2 MeSH |
| 650 | _ | 2 | |a Induced Pluripotent Stem Cells: metabolism |2 MeSH |
| 650 | _ | 2 | |a MTOR Inhibitors |2 MeSH |
| 650 | _ | 2 | |a Acid Ceramidase: genetics |2 MeSH |
| 650 | _ | 2 | |a Acid Ceramidase: metabolism |2 MeSH |
| 650 | _ | 2 | |a Glucosylceramidase: genetics |2 MeSH |
| 650 | _ | 2 | |a Glucosylceramidase: metabolism |2 MeSH |
| 650 | _ | 2 | |a Gaucher Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a Dopaminergic Neurons: metabolism |2 MeSH |
| 650 | _ | 2 | |a TOR Serine-Threonine Kinases: genetics |2 MeSH |
| 650 | _ | 2 | |a Mechanistic Target of Rapamycin Complex 1: genetics |2 MeSH |
| 650 | _ | 2 | |a Mutation |2 MeSH |
| 650 | _ | 2 | |a Lysosomes: metabolism |2 MeSH |
| 700 | 1 | _ | |a Srikanth, Manasa P |b 1 |
| 700 | 1 | _ | |a Deleidi, Michela |0 P:(DE-2719)2810385 |b 2 |u dzne |
| 700 | 1 | _ | |a Hallett, Penelope J |b 3 |
| 700 | 1 | _ | |a Isacson, Ole |b 4 |
| 700 | 1 | _ | |a Feldman, Ricardo A |0 0000-0001-6090-0439 |b 5 |
| 773 | _ | _ | |a 10.1093/hmg/ddad025 |g Vol. 32, no. 11, p. 1888 - 1900 |0 PERI:(DE-600)1474816-2 |n 11 |p 1888 - 1900 |t Human molecular genetics |v 32 |y 2023 |x 0964-6906 |
| 856 | 4 | _ | |u https://pub.dzne.de/record/258096/files/DZNE-2023-00558%20SUP.zip |
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