GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Jesús, Silvia; Huertas, Ismael; Bernal‐Bernal, Inmaculada; Bonilla‐Toribio, Marta; Cáceres‐Redondo, María T.; Vargas‐González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, E.; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

doi:10.1371/journal.pone.0167749

Cited by 91 publications

(144 citation statements)

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“…The finding that disease risk and clinical characteristics in PD and DLB seem dependent on GBA1 mutation severity are consistent with previous reports . We now show for both disease entities that CSF biomarker profiles of total alpha‐synuclein also seem dependent on mutation severity.…”

Section: Discussionsupporting

confidence: 92%

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

et al. 2019

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Background Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha‐synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease‐modifying treatment options such as alpha‐synuclein lowering compounds are under way, patient stratification according to alpha‐synuclein‐specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. Objective Are GBA1 mutations associated with a CSF alpha‐synuclein profile in PD? Methods Screening of the GBA1 gene and analysis of CSF levels of total alpha‐synuclein were performed in 80 PDGBA, 80 PDGBA_wildtype and 39 healthy controls cross‐sectionally. Subgroup analyses based on mutation severity was done for PDGBA. Results Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha‐synuclein. Conclusion The effects of GBA1 mutations on CSF alpha‐synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 92%

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

et al. 2019

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“…In addition to cognitive decline, various other nonmotor symptoms including REM sleep behavior disorder, hyposmia, and autonomic dysfunction seem to be more frequent [14]. Interestingly, it has recently been demonstrated that also the E326K variant predicts a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD [15].…”

Section: Discussionmentioning

confidence: 99%

The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal

Berge-Seidl

Pihlstrøm

Maple‐Grødem

et al. 2017

Neuroscience Letters

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Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genomewide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods:We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls).Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium between the variants.Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p=0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p=0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p=0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses of the pairwise LD revealed that E326K and rs35749011 are in very high LD (r 2 0.95). Conclusions:Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS studies of PD.

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“…GBA1 heterozygotes have an earlier age at onset compared with noncarriers of 3‐6 years for PD and 5‐7 years for DLB, respectively. Mean age at onset in heterozygous PD carriers is about 50‐55 years .…”

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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GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Cited by 91 publications

References 45 publications

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

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