title: CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy.
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.
authors: Genzyme Corporation, Framingham, MA 01701, USA. pablo.sardi@genzyme.com
authors: S Pablo
authors: SP
authors: Sardi
authors: Jennifer
authors: J
authors: Clarke
authors: Cathrine
authors: C
authors: Kinnecom
authors: Thomas J
authors: TJ
authors: Tamsett
authors: Lingyun
authors: L
authors: Li
authors: Lisa M
authors: LM
authors: Stanek
authors: Marco A
authors: MA
authors: Passini
authors: Gregory A
authors: GA
authors: Grabowski
authors: Michael G
authors: MG
authors: Schlossmacher
authors: Richard L
authors: RL
authors: Sidman
authors: Seng H
authors: SH
authors: Cheng
authors: Lamya S
authors: LS
authors: Shihabuddin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D000229:Dependovirus; D019286:Endopeptidase K / Q000378:metabolism; D005776:Gaucher Disease / Q000378:metabolism / Q000473:pathology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D007150:Immunohistochemistry; D051379:Mice; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase; D019286:Endopeptidase K