Human molecular geneticsNov 12, 2025

Blocking or lowering ASAH1 enzyme helps clear α-synuclein in dopamine neurons with GBA1 mutations from Parkinson’s patients

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Reducing ASAH1/acid ceramidase restored alpha-synuclein clearance-related lysosomal pathways in GBA1-mutant Parkinson's dopamine neurons.

Evidence

A patient hiPSC-derived dopamine-neuron study compared heterozygous GBA1 Parkinson's neurons with isogenic controls and tested inhibitors plus CRISPR/Cas9 ASAH1 knockdown.

Caveat

The evidence comes from a cell model, not animal or human treatment testing, so ASAH1 remains a proposed therapeutic target.

Simplified

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 () 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 heterozygote GBA1 mutations to examine the role of ACDase in promoting α-synuclein accumulation and aggregation, a hallmark of PD. Compared to isogenic controls, hiPSC-derived PD dopamine (DA) neurons had elevated levels of pathogenic α-synuclein species. There was also reduced nuclear localization of transcription factor EB (), impaired autophagy, and decreased levels of cathepsin D (CathD), a lysosomal protease involved in α-synuclein degradation [11]. Treatment of the mutant DA neurons with a number of different ACDase inhibitors, or CRISPR/Cas9 knockdown (KD) of the ASAH1 gene, reversed all the phenotypic abnormalities of the mutant DA neurons. We conclude that in GBA1/PD-DA neurons, ACDase contributes to deregulation of key nodes of the autophagy/lysosomal pathway (ALP) involved in α-synuclein clearance. Our results suggest that ACDase is a potential therapeutic target for treating GBA1-associated PD.

Key numbers

40%–50%

Reduction in GCase Activity

Mutant dopamine neurons showed reduced GCase enzymatic activity compared to isogenic controls.

50%

Effect

of resulted in a significant decrease in α-synuclein levels.

60%

Expression Increase

inhibition resulted in increased levels in mutant dopamine neurons.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Blocking or lowering ASAH1 enzyme helps clear α-synuclein in dopamine neurons with GBA1 mutations from Parkinson’s patients

Abstract

Key numbers

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Key numbers

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief