Dermal fibroblasts from patients with Parkinson's disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations.

Lucy M Collins,Janelle Drouin-Ouellet,Timothy Cox,Wei-Li Kuan,Roger A Barker

doi:10.12688/f1000research.12090.2

Lucy M Collins, Janelle Drouin-Ouellet + Show 3 more

Open Access

https://doi.org/10.12688/f1000research.12090.2

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Abstract

Background: Recently, the development of Parkinson's disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

Highlights

Gaucher disease (GD) is an autosomal recessive condition that is caused by defective glucocerebrosidase (GCase) enzyme
To clarify figure E in the case of Parkinson’s disease (PD)/GD and GD the GCase protein and activity was reduced which was expected, in the Parkinson’s disease GBA carriers (PD GBA) the protein amount was not reduced but the activity was reduced in this case, this leads us to believe in the case of PD GBA there is an additional factor, outside the GCase protein, causing pathology in these cells which could lead to dysfunction
GCase activity is decreased in patient fibroblasts carrying a GBA mutation We started by assessing enzyme activity as an indication of overall lysosomal health and the extent to which this is restricted to GCase activity

Summary

Introduction

Gaucher disease (GD) is an autosomal recessive condition that is caused by defective glucocerebrosidase (GCase) enzyme. GCase (GBA gene) normally functions to breakdown lipids in the lysosomes and mutations in GCase cause accumulation of its substrate, glucoceramide (GlcCer). GCase (GBA gene) normally functions to breakdown lipids in the lysosomes and mutations in GCase cause accumulation of its substrate, glucoceramide (GlcCer)1 These mutations result in characteristic engorged macrophages, known as Gaucher macrophages (GMs) or ‘Gaucher cells’. The development of Parkinson’s disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Keywords GBA mutations, Parkinson’s disease, Gaucher disease, fibroblasts, lysosome, autophagy version 2 (revision) 09 Feb 2018.

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