Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies

Clark, Lorraine N.; Kartsaklis, Lykourgos A.; Gilbert, Rebecca M.; Dorado, Beatriz; Ross, Barbara; Kisselev, Sergey; Verbitsky, Miguel; Mejia‐Santana, Helen; Côté, Lucien J.; Andrews, Howard; Vonsattel, Jean‐Paul; Fahn, Stanley; Mayeux, Richard; Honig, Lawrence S.; Marder, Karen

doi:10.1001/archneurol.2009.54

Cited by 181 publications

(189 citation statements)

References 24 publications

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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

314

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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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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

314

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“…In a study of brain samples from patients with PD and DLB, samples with a homozygous GBA1 mutation showed that > 80 % of the LBs were co-localized with GCase, and those with a heterozygous GBA1 mutation showed a 75 % GCase co-localization rate (range, 32 -90 % ) with LBs, compared to a mean of 4 % in patients with PD and DLB without a GBA1 mutation (Goker -Alpan et al, 2010 ). In addition, patients with GD and GD carriers with Parkinsonism have LB pathology (Clark et al , 2009 ). GBA1 mutation carriers tend to have more cortical LBs (82 % ) than those of non-carriers (43 % ; p < 0.001) (Clark et al , 2009 ).…”

Section: Gba1 Mutations and Lewy Body Pathologymentioning

confidence: 94%

“…GBA1 mutations were found in 28 % of patients with DLB, 10 % of patients with Alzheimer ' s disease (AD), and 3 % of controls ( p < 0.001) (Clark et al , 2009 ). Although GBA1 mutation frequency in patients with AD is lower than that in patients with LBDs, it is still higher than in control individuals.…”

Section: Gba1 Mutations In Parkinson ' S Diseasementioning

confidence: 98%

“…In addition, patients with GD and GD carriers with Parkinsonism have LB pathology (Clark et al , 2009 ). GBA1 mutation carriers tend to have more cortical LBs (82 % ) than those of non-carriers (43 % ; p < 0.001) (Clark et al , 2009 ). This finding suggests that Parkinsonism-associated GCase mutants may promote α -synuclein aggregation directly, and have active roles in LB formation.…”

Section: Gba1 Mutations and Lewy Body Pathologymentioning

confidence: 98%

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Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Yang

Lee

Lee³

et al. 2013

Biological Chemistry

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Mutations in the gene encoding glucocerebrosidase ( GBA1 ) cause Gaucher disease (GD), a lysosomal storage disease with recessive inheritance. Glucocerebrosidase (GCase) is a lysosomal lipid hydrolase that digests glycolipid substrates, such as glucosylceramide and glucosylsphingosine. GBA1 mutations have been implicated in Lewy body diseases (LBDs), such as Parkinson ' s disease and dementia with Lewy bodies. Parkinsonism occurs more frequently in certain types of GD, and GBA1 mutation carriers are more likely to have LBDs than noncarriers. Furthermore, GCase is often found in Lewy bodies, which are composed of α -synuclein fibrils as well as a variety of proteins and vesicles. In this review, we discuss potential mechanisms of action of GBA1 mutations in LBDs with particular emphasis on α -synuclein aggregation by reviewing the current literature on the role of GCase in lysosomal functions and glycolipid metabolism.

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“…In the past decade, molecular genetic studies have revealed genetic variants (both simple mutations and copy-number variations (CNVs)) associated with DLB in genes previously reported to be implicated in classic forms of AD (AβPP [10], PSEN1 [11], PSEN2 [12], PRNP [13]) or in Parkinson's disease (PD) (SNCA [14][15][16], SNCB [17], LRRK2 [18,19], GBA [20][21][22][23]). However, mutations in these genes explain only a small number of clinically diagnosed DLB patients.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

Meeus

Nuytemans

Crosiers

et al. 2010

JAD

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Abstract. The second most frequent form of neurodegenerative dementia after Alzheimer's disease is dementia with Lewy bodies (DLB). Since informative DLB families are scarce, little is presently known about the molecular genetic etiology of DLB. We recently mapped the first locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsy-proven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within the DLB region did not identify a simple pathogenic mutation that co-segregated with disease in family DR246. Also high resolution analysis of copy number variations in the DLB locus did not provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36 as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not identify the pathogenic mutation in family DR246. Other detection strategies will be needed to reveal the underlying mutation explaining the linkage of DLB to 2q35-q26. Possibly the disease mutation in this family acts through a more complex mechanism than generally envisaged for monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an entry point into the pathogenic cascades underlying DLB pathology.

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Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies

Cited by 181 publications

References 24 publications

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

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

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