A “dose” effect of mutations in the GBA gene on Parkinson's disease phenotype

Thaler, Avner; Gurevich, Tanya; Shira, Anat Bar; Weisz, Mali Gana; Ash, Elissa; Shiner, Tamara; Orr-Urtreger, Avi; Giladi, Nir; Mirelman, Anat

doi:10.1016/j.parkreldis.2016.12.014

Cited by 86 publications

(85 citation statements)

References 27 publications

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“…Lastly, individuals with GD are also at risk of developing PD. The risk attributed to homozygous GBA1 loss‐of‐function alleles is significantly greater than that observed in heterozygous GBA1 mutations, although most individuals with GD will still not get PD . Together, the accumulating evidence for genotype‐phenotype relationships in GBA‐PD strongly support a dose‐dependent, loss‐of‐function risk model.…”

Section: Glucocerebrosidase (Gba1)mentioning

confidence: 96%

“…Specifically, carriers of more severe mutations, such as the c.84dupG or L444P mutation, which are often associated with neuronopathic GD, are more likely to develop PD than carriers of N370S of E326K mutations . Moreover, stronger GBA1 loss‐of‐function alleles have also been implicated with more severe motor phenotypes and increased risk of nonmotor manifestations, including hyposmia, cognitive impairment, and dementia . Interestingly, reduced GCase enzymatic activity has also been documented in sporadic PD (without known GBA1 mutations) .…”

Section: Glucocerebrosidase (Gba1)mentioning

confidence: 99%

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Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal‐recessive or X‐linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult‐onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Glucocerebrosidase (Gba1)mentioning

confidence: 96%

Section: Glucocerebrosidase (Gba1)mentioning

confidence: 99%

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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“…10,[47][48][49]54,61,62,66 Among GBA1 carriers who develop PD, homozygotes have a 6-to 11-year earlier onset than heterozygotes. 53,67,68 In PD, the onset occurs at a younger age among heterozygous carriers of severe versus mild GBA1 mutations, ranging from 2 to 13 years 10,49,62 (Table 1).…”

Section: Clinical and Neuroimaging Features Of Gba-related Synucleinomentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

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“…Heterozygous mutations in GBA1, the gene mutated in Gaucher disease, encoding the lysosomal enzyme glucocerebrosidase (GCase, EC 3.2.1.45) are the most common genetic risk factor for Parkinson disease as well as dementia with Lewy bodies, often associated with an earlier onset and more severe cognitive and non-motor symptoms [10,11]. Severe GBA1 mutations, such as loss of function mutations c.84insG and IVS2+1G > A, confer a higher risk for Parkinson disease and a more progressive course compared to milder mutations like N409S (N370S) [12,13]. Many groups have investigated the relationship between SNCA levels and GCase deficiency or inhibition, but only a few have utilized animal models [14–17], including mice treated with the GCase inhibitor conduritol-β-epoxide (CBE) [16,18].…”

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Tayebi

Parisiadou

Berhe

et al. 2017

Molecular Genetics and Metabolism

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Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.

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A “dose” effect of mutations in the GBA gene on Parkinson's disease phenotype

Cited by 86 publications

References 27 publications

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

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