Pharmacological GCase Activity Enhancement Inhibits Tau Accumulation

Author:

Ciccaldo MatteoORCID,Pérez-Carmona Natàlia,Piovesana Ester,Cano-Crespo Sara,Ruano Ana,Delgado Aida,Fregno IlariaORCID,Guzmán Beatriz Calvo-Flores,Bellotto Manolo,Molinari MaurizioORCID,Taylor Joanne,Papin Stéphanie,García-Collazo Ana María,Paganetti PaoloORCID

Abstract

AbstractA 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 diseaseGBA1mutations 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 theGBA1product GCase augmented Tau-dependent lysosomal stress and Tau accumulation. Here, we show increased Tau seed-induced Tau accumulation in Gaucher’s fibroblasts carryingGBA1mutations when compared to normal fibroblasts. Pharmacological enhancement of GCase reversed this effect, notably, also in normal fibroblasts. This suggests that boosting GCase activity may represent a therapeutic strategy to slow down aging-dependent lysosomal deficits and brain protein deposition.

Publisher

Cold Spring Harbor Laboratory

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