Session Information
Date: Monday, October 8, 2018
Session Title: Parkinson's Disease: Pathophysiology
Session Time: 1:15pm-2:45pm
Location: Hall 3FG
Objective: To study the pharmacological modulation of glucocerebrosidase activity in the Thy1-aSYN mouse model of Parkinson’s disease (PD).
Background: PD is a complex neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and chronic neuroinflammation. Carrying a mutated allele of GBA1 is one of the most frequent risk factors for PD. GBA1 encodes the enzyme glucocerebrosidase that breaks down glucocerebrosides into glucose and ceramide inside lysosomes. How glucocerebrosidase defects lead to increased PD risk is not elucidated. A reduction in glucocerebrosidase activity has been reported in the brain of PD patients, carrying or not a GBA1 mutation.
Methods: In this study, we used conduritol-beta-epoxyde (CBE), an irreversible competitive inhibitor of glucocerebrosidase, to model a decrease of glucocerebrosidase activity in transgenic mice overexpressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice).
Results: Daily administration of CBE (intraperitoneal injection, 100mg/kg/day) decreased glucocerebrosidase enzymatic activity and caused an accumulation of glucocerebrosides in the brain of Thy1-aSYN mice and wild-type littermates, as measured by fluorogenic assay and mass spectrometry, respectively. CBE-treated transgenic animals showed decreased performance in the adhesive removal test. CBE-treated transgenic animals also presented an increased number of CD11b+/CD45low (e.g. microglia) in the brain as numbered by multicolor flow cytometry.
Conclusions: Altogether, our data support that the reduction of glucocerebrosidase activity worsens sensory-motor deficits and chronic neuroinflammation in the Thy1-aSYN mouse model. Analyses of key immune factors and alpha-synuclein proteins will further determine whether enhancing lysosomal glucocerebrosidase enzymatic activity is an interesting pharmacological strategy against Parkinson’s disease.
To cite this abstract in AMA style:
K. Belarbi, E. Cuvelier, H. Carrie, M.A. Bonte, W. Sibran, C. Leghay, J. Von Gerichten, V. Nordström, R. Sandhoff, T. Comptdaer, N. Jouy, E. Mutez, A. Destee, C. Pincon, B. Gressier, M.C. Chartier-Harlin. Pharmacological modulation of lysosomal glucocerebrosidase activity in the Thy1-aSYN mouse model of Parkinson’s disease [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/pharmacological-modulation-of-lysosomal-glucocerebrosidase-activity-in-the-thy1-asyn-mouse-model-of-parkinsons-disease/. Accessed May 18, 2025.« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacological-modulation-of-lysosomal-glucocerebrosidase-activity-in-the-thy1-asyn-mouse-model-of-parkinsons-disease/