CNS expression of glucocerebrosidase corrects [alpha]-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 29; p. 12101
• Main Authors: Sardi, S Pablo, Clarke, Jennifer, Kinnecom, Cathrine, Tamsett, Thomas J, Li, Lingyun, Stanek, Lisa M, Passini, Marco A, Grabowski, Gregory A, Schlossmacher, Michael G, Sidman, Richard L, Cheng, Seng H, Shihabuddin, Lamya S
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 19.07.2011
• Subjects: Animal memory; Gene expression; Genetic disorders; Parkinson's disease; Rodents
• ISSN: 0027-8424; 1091-6490

Emerging genetic and clinical evidence suggests a link between Gaucher disease and the synucleinopathies Parkinson disease and dementia with Lewy bodies. Here, we provide evidence that a mouse model of Gaucher disease (Gba1^D409V/D409V) exhibits characteristics of synucleinopathies, including progressive accumulation of proteinase K-resistant α-synuclein/ubiquitin aggregates in hippocampal neurons and a coincident memory deficit. Analysis of homozygous (Gba1^D409V/D409V) and heterozygous (Gba1^D409V/+ and Gba1+/-) Gaucher mice indicated that these pathologies are a result of the combination of a loss of glucocerebrosidase activity and a toxic gain-of-function resulting from expression of the mutant enzyme. Importantly, adeno-associated virus-mediated expression of exogenous glucocerebrosidase injected into the hippocampus of Gba1^D409V/D409V mice ameliorated both the histopathological and memory aberrations. The data support the contention that mutations in GBA1 can cause Parkinson disease-like α-synuclein pathology, and that rescuing brain glucocerebrosidase activity might represent a therapeutic strategy for GBA1-associated synucleinopathies. [PUBLICATION ABSTRACT]