Objective: To investigate the link between lipid dysregulation and lysosomal dysfunction in GBA-associated Parkinson’s disease (GBA-PD) and explore potential metabolic rescue strategies.

Background: Mutations in the GBA gene are the most common genetic risk factor for PD, leading to impaired α-synuclein clearance. While glycosphingolipid accumulation is well-studied, the role of other lipids, particularly cholesterol, in GBA-PD lysosomal dysfunction remains poorly understood.

Method: We compared systemic lipid profiles between a clinical cohort of GBA-PD and genetically undefined PD patients. A novel GBA-PD mouse model was utilized to recapitulate chronic disease progression. Mechanisms were investigated using unbiased lysosomal proteomics and autophagic flux analysis. Targeted interventions, including metabolic supplementation and viral-mediated gene delivery, were evaluated for therapeutic efficacy.

Results: Clinical analysis revealed distinct lipid deficiencies in GBA-PD patients that correlated with disease status. In our experimental models, lysosomal proteomics identified a significant loss of specific lipid-rich microdomains and impaired organelle interactions. We found that GBA deficiency leads to a reduction in key transcriptional regulators of lipid synthesis, resulting in compromised autophagosome-lysosome fusion. Supplementing these deficient lipid components or genetically restoring their biosynthetic pathways effectively enhanced autophagic flux and significantly reduced α-synuclein accumulation both in vitro and in vivo.

Conclusion: Our findings reveal a novel lipid-dependent mechanism underlying lysosomal dysfunction in GBA-PD. Restoring specific lipid homeostasis presents a promising therapeutic strategy for mitigating α-synuclein pathology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dysregulation-of-lysosomal-lipid-microdomains-impairs-autophagic-flux-in-gba-associated-parkinsons-disease/