Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2011-07, Vol.108 (29), p.12101-12106

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (Gba1D409V/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 (Gba1D409V/D409V) and heterozygous (Gba1D409V/+ 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 Gba1D409V/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.