ParkinsonCanadaV1, Main, Exploration, bibRecord, 001711

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

Identifieur interne : 001711 ( Main/Exploration ); précédent : 001710; suivant : 001712

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

Auteurs : S. Pablo Sardi [États-Unis] ; Jennifer Clarke [États-Unis] ; Cathrine Kinnecom [États-Unis] ; Thomas J. Tamsett [États-Unis] ; Lingyun Li [États-Unis] ; Lisa M. Stanek [États-Unis] ; Marco A. Passini [États-Unis] ; Gregory A. Grabowski [États-Unis] ; Michael G. Schlossmacher [Canada] ; Richard L. Sidman [États-Unis] ; Seng H. Cheng [États-Unis] ; Lamya S. Shihabuddin [États-Unis]

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2011.

RBID : PMC:3141921

Abstract

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141921

DOI: 10.1073/pnas.1108197108
PubMed: 21730160
PubMed Central: 3141921

Affiliations:

Canada, États-Unis
Massachusetts, Ohio

Le document en format XML

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 K1H 8M5</nlm:aff>
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 K1H 8M5</nlm:aff>
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<front><div type="abstract" xml:lang="en"><p>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 (<italic>Gba1<sup>D409V/D409V</sup>
</italic>
) 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 (<italic>Gba1<sup>D409V/D409V</sup>
</italic>
) and heterozygous (<italic>Gba1<sup>D409V/+</sup>
</italic>
 and <italic>Gba1<sup>+/−</sup>
</italic>
) 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 <italic>Gba1<sup>D409V/D409V</sup>
</italic>
 mice ameliorated both the histopathological and memory aberrations. The data support the contention that mutations in <italic>GBA1</italic>
 can cause Parkinson disease-like α-synuclein pathology, and that rescuing brain glucocerebrosidase activity might represent a therapeutic strategy for <italic>GBA1</italic>
-associated synucleinopathies.</p>
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La maladie de Parkinson au Canada (serveur d'exploration)

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

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

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	La maladie de Parkinson au Canada (serveur d'exploration)
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