Significant study of population stratification, sensitivity analysis and trim and fill analyses on <i>GBA</i> mutation and parkinson's disease

Liu, Jie

doi:10.1002/ajmg.b.32214

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…The study reported an overall odds ratio of 5.43 for carrying any GBA mutation in PD patients when compared with controls . The association between GBA mutations and PD has been confirmed in large‐scale comprehensive meta‐analyses . The GBA gene encodes for GCase, which catalyzes the conversion of glucosylceramide into glucose and ceramide.…”

Section: Lsds and The Emerging Role Of Lysosomal Dysfunction In Pdmentioning

confidence: 84%

“…55 The association between GBA mutations and PD has been confirmed in large-scale comprehensive meta-analyses. 56,57 The GBA gene encodes for GCase, which catalyzes the conversion of glucosylceramide into glucose and ceramide. Aggregation of a-synuclein in brains from patients with GBA1-associated parkinsonism and the detection of GCase as a component of LBs in PD patients suggested that GCase dysfunction contributes to PD-like pathological inclusions.…”

Section: Lsds and The Emerging Role Of Lysosomal Dysfunction In Pdmentioning

confidence: 99%

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Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

et al. 2016

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Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.

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Section: Lsds and The Emerging Role Of Lysosomal Dysfunction In Pdmentioning

confidence: 84%

Section: Lsds and The Emerging Role Of Lysosomal Dysfunction In Pdmentioning

confidence: 99%

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

et al. 2016

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“…Although parkinsonism is a rare feature in patients with GD, several GD patients with parkinsonism had relatives with a typical, late-onset form of PD [ 32 ]. After confirmation of this observation in large-scale multicenter studies [ 33 ] and meta-analyses [ 34 , 35 ], the presence of pathogenic heterozygous mutations in this gene is now considered as one of the most important risk factors to develop PD. It is estimated that the prevalence of PD patients with GBA mutations is 5–10%, while this percentage can be higher in certain populations [ 36 ].…”

Section: Converging Evidence For a Role Of Alp Dysfunction In Pdmentioning

confidence: 98%

Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease

Moors

Hoozemans

Ingrassia

et al. 2017

Mol Neurodegeneration

234

182

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Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson’s Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn). As autophagy is one of the main systems involved in the proteolytic degradation of α-syn, pharmacological enhancement of autophagy may be an attractive strategy to combat α-syn aggregation in PD. Here, we review the potential of autophagy enhancement as disease-modifying therapy in PD based on preclinical evidence. In particular, we provide an overview of the molecular regulation of autophagy and targets for pharmacological modulation within the ALP. In experimental models, beneficial effects on multiple pathological processes involved in PD, including α-syn aggregation, cell death, oxidative stress and mitochondrial dysfunction, have been demonstrated using the autophagy enhancers rapamycin and lithium. However, selectivity of these agents is limited, while upstream ALP signaling proteins are involved in many other pathways than autophagy. Broad stimulation of autophagy may therefore cause a wide spectrum of dose-dependent side-effects, suggesting that its clinical applicability is limited. However, recently developed agents selectively targeting core ALP components, including Transcription Factor EB (TFEB), lysosomes, GCase as well as chaperone-mediated autophagy regulators, exert more specific effects on molecular pathogenetic processes causing PD. To conclude, the targeted manipulation of downstream ALP components, rather than broad autophagy stimulation, may be an attractive strategy for the development of novel pharmacological therapies in PD. Further characterization of dysfunctional autophagy in different stages and molecular subtypes of PD in combination with the clinical translation of downstream autophagy regulation offers exciting new avenues for future drug development.

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“…Many studies have shown an increased frequency of GBA variants in PD compared to controls. [2][3][4] GBA variants were shown to confer a fiveto seven-fold increased risk of PD 4,5 and to modify PD manifestations, causing earlier age of onset, more severe cognitive dysfunction, and accelerated progression of the neurodegenerative process. [6][7][8] Concerning the mechanism relating GBA variants to PD, it has been suggested that either a chronic loss of enzymatic activity or a possible toxic gain of function of the mutated glucocerebrosidase results in lysosomal dysfunction and endoplasmic reticulum stress could contribute to disease pathogenesis.…”

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confidence: 99%

Role of Lysosomal Gene Variants in Modulating GBA‐Associated Parkinson's Disease Risk

et al. 2022

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Background To date, variants in the GBA gene represent the most frequent large‐effect genetic factor associated with Parkinson's disease (PD). However, the reason why individuals with the same GBA variant may or may not develop neurodegeneration and PD is still unclear. Objectives Therefore, we evaluated the contribution of rare variants in genes responsible for lysosomal storage disorders (LSDs) to GBA‐PD risk, comparing the burden of deleterious variants in LSD genes in PD patients versus asymptomatic subjects, all carriers of deleterious variants in GBA. Methods We used a custom next‐generation sequencing panel, including 50 LSD genes, to screen 305 patients and 207 controls (discovery cohort). Replication and meta‐analysis were performed in two replication cohorts of GBA‐variant carriers, of 250 patients and 287 controls, for whom exome or genome data were available. Results Statistical analysis in the discovery cohort revealed a significantly increased burden of deleterious variants in LSD genes in patients (P = 0.0029). Moreover, our analyses evidenced that the two strongest modifiers of GBA penetrance are a second variation in GBA (5.6% vs. 1.4%, P = 0.023) and variants in genes causing mucopolysaccharidoses (6.9% vs. 1%, P = 0.0020). These results were confirmed in the meta‐analysis, where we observed pooled odds ratios of 1.42 (95% confidence interval [CI] = 1.10–1.83, P = 0.0063), 4.36 (95% CI = 2.02–9.45, P = 0.00019), and 1.83 (95% CI = 1.04–3.22, P = 0.038) for variants in LSD genes, GBA, and mucopolysaccharidosis genes, respectively. Conclusion The identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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Significant study of population stratification, sensitivity analysis and trim and fill analyses on GBA mutation and parkinson's disease

Cited by 11 publications

References 30 publications

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease

Role of Lysosomal Gene Variants in Modulating GBA‐Associated Parkinson's Disease Risk

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