Journal Article

DZNE-2023-00558

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.

Kumar, M. ; Srikanth, M. P. ; Deleidi, M.DZNE* ; Hallett, P. J. ; Isacson, O. ; Feldman, R. A.

2023
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/hmg/ddad025

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.

Keyword(s): Humans (MeSH) ; Parkinson Disease: metabolism (MeSH) ; alpha-Synuclein: genetics (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; MTOR Inhibitors (MeSH) ; Acid Ceramidase: genetics (MeSH) ; Acid Ceramidase: metabolism (MeSH) ; Glucosylceramidase: genetics (MeSH) ; Glucosylceramidase: metabolism (MeSH) ; Gaucher Disease: metabolism (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; TOR Serine-Threonine Kinases: genetics (MeSH) ; Mechanistic Target of Rapamycin Complex 1: genetics (MeSH) ; Mutation (MeSH) ; Lysosomes: metabolism (MeSH) ; alpha-Synuclein ; MTOR Inhibitors ; Acid Ceramidase ; Glucosylceramidase ; TOR Serine-Threonine Kinases ; Mechanistic Target of Rapamycin Complex 1

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Contributing Institute(s):

1. Mitochondria and Inflammation in Neurodegeneration (AG Deleidi)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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