A novel allosteric GCase modulator prevents Tau accumulation in GBA1^WT and GBA1^L444P/L444P cellular models.

ABSTRACT: A slow decline in the autophagy-lysosomal pathway is a hallmark of the normal aging brain. Yet, an acceleration of this cellular function may propel neurodegenerative events. In fact, mutations in genes associated with the autophagy-lysosomal pathway can lead to Parkinson's disease. Also, amyloidogenic protein deposition is observed in lysosomal storage disorders, which are caused by genetic mutations representing risk factors for Parkinson's disease. For example, Gaucher's disease GBA1 mutations leading to defects in lysosomal sphingolipid metabolism cause α-synuclein accumulation. We observed that increased lysosomal Tau accumulation is found in human dermal fibroblasts engineered for inducible Tau expression. Inhibition of the GBA1 product GCase augmented Tau-dependent lysosomal stress

SUBMITTER: Ciccaldo M 

PROVIDER: S-EPMC12095489 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature