Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease

Clark, Lorraine N.; Ross, Barbara; Wang, Y.; Mejia‐Santana, Helen; Harris, Juliette; Louis, Elan D.; Côté, Lucien J.; Andrews, Howard; Fahn, Stanley; Waters, Cheryl; Ford, Blair; Frucht, Steven J.; Ottman, Ruth; Marder, Karen

doi:10.1212/01.wnl.0000276989.17578.02

Cited by 230 publications

(244 citation statements)

References 46 publications

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“…In addition, GBA1-null mutations (84GG or IVS2+1) are associated with the highest risk for synucleinopathies, whereas a putative folding mutation N370S having the highest residual activity presents the lowest risk (38). Hence, the data suggest that mutations in GBA1 are sufficient to initiate aberrant α-syn folding but decrease in glucocerebrosidase activity (regardless of mutations) seems to accelerate misprocessing, and thereby increase the susceptibility and cause earlier onset of PD-like changes (8,39).…”

Section: Discussionmentioning

confidence: 91%

“…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%

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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.

296

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: Discussionmentioning

confidence: 91%

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.

296

314

View full text Add to dashboard Cite

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“…However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72]. It has been reported that there is significantly higher frequency of usage of acetylcholine esterase inhibitors for dementia in GBA PD compared with idiopathic PD [73], and one study found significant differences in selfreported cognitive impairment [74].…”

Section: Non Motor Featuresmentioning

confidence: 99%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

105

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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“…For example, the average age of initial diagnosis for GBA1 mutation carriers is 4 years younger than that of non-carriers (Aharon -Peretz et al, 2004 ;Clark et al , 2007 ;Neumann et al , 2009 ). Moreover, more cognitive impairment, and less resting tremor and bradykinesia are reported in the PD of GBA1 mutation carriers (Goker -Alpan et al, 2008 ;Sidransky et al , 2009 ).…”

Section: Gba1 Mutations In Parkinson ' S Diseasementioning

confidence: 99%

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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Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease

Abstract: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.

Cited by 230 publications

References 46 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 Mutations in Parkinson Disease

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

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