The Spectrum of Parkinsonian Manifestations Associated With Glucocerebrosidase Mutations

Göker-Alpan, Özlem; Lopez, Grisel; Vithayathil, Joseph; Davis, Joie; Hallett, Mark; Sidransky, Ellen

doi:10.1001/archneur.65.10.1353

Cited by 185 publications

(158 citation statements)

References 32 publications

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“…Thus, while homozygous GBA mutations cause Gaucher's disease, heterozygous GBA mutations appear to increase risk of PD. Heterozygous GBA mutations have also been identified in patients with DLB [268,269].…”

Section: Susceptibility Genesmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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Section: Susceptibility Genesmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…Emerging evidence suggests that mutations in GBA1 are the most common genetic risk factor for synucleinopathies, such as Parkinson disease (PD) and dementia with Lewy bodies (DLB), acting to modify the age of onset and disease progression (6)(7)(8)(9)(10)(11)(12)(13). The nervous system of subjects with PD and DLB typically shows abnormal accumulation of α-synuclein (α-syn) in Lewy bodies (LB) and Lewy neurites (LN) (14).…”

Section: D409v/d409vmentioning

confidence: 99%

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

Sardi

Clarke

Kinnecom

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

292

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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.

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“…GD is an autosomal recessive lipidosis resulting from a deficiency of glucocerebrosidase enzyme. The observation of patients with GD and parkinsonism (Tayebi et al, 2003, Goker-Alpan et al, 2008, the increased rate of GBA mutations and polymorphism in PD patients ) along with neuropathological findings in brain of GD patients with parkinsonism similar to PD and DLB, all strengthening this hypothesis. The deficit in GBA might act through an impaired degradation of proteins via lysosomes leading to abnormal protein aggregates and Lewy bodies formation.…”

Section: Impaired Protein Degradationmentioning

confidence: 66%