Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.

ABSTRACT: Bi-allelic mutations in GBA1, a gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase), cause Gaucher disease (GD). Although GD carriers do not exhibit clinical manifestations, GBA1 mutations are the highest risk factor for Parkinson's disease (PD) in GD patients and carriers of the disease [1-5]. GCase breaks down glucosylceramide (GluCer), a sphingolipid that accumulates in GD. GluCer is deacylated by the lysosomal enzyme acid ceramidase (ACDase) to glucosylsphingosine (GluSph) [6-8]. GluSph is neurotoxic and accumulates to high levels in neuronopathic GD brains [9, 10]. However, whether this metabolic pathway involving ACDase plays a role in GBA1-associated PD (GBA1/PD) is not known. In this report we used induced pluripotent stem cells (hiPSCs) from PD patients harboring h

SUBMITTER: Kumar M 

PROVIDER: S-EPMC12680604 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature