The association between the LRRK2 G2385R variant and the risk of Parkinson’s disease: a meta-analysis based on 23 case–control studies

Xie, Chenglong; Pan, Jialin; Wang, Wenwen; Zhang, Yu; Zhang, Sufang; Gan, Jing; Liu, Zhenguo

doi:10.1007/s10072-014-1878-2

Cited by 29 publications

(18 citation statements)

References 45 publications

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“…Importantly, strong genetic association suggests that the missense substitution of glycine 2385 to arginine (G2385R) within the C-terminal WD40 domain is a pathologically relevant variant. The G2385R variant is associated with an increased risk of developing idiopathic PD in Chinese Han and Korean ethnicity 20–22 . We show here that the G2385R variant alters the LRRK2-associated protein interactome and reduces its binding to SV.…”

Section: Introductionmentioning

confidence: 99%

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

Carrión

Marsicano

Daniele

et al. 2017

Sci Rep

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Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson’s disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.

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Section: Introductionmentioning

confidence: 99%

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

Carrión

Marsicano

Daniele

et al. 2017

Sci Rep

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“…The used LRRK2 translational model most closely approximates human LRRK2 G2385R mutation, which occurs in the human WD40 domain and is a risk factor for PD, mainly in Asian populations [21]. …”

Section: Discussionmentioning

confidence: 99%

“…Two more common variations in the LRRK2 gene have been described: G2019S and G2385R [19]. Among them, the most common (G2019S) accounts for 3–6% of familial dominant PD and for 1-2% of sporadic forms with a north-south gradient of G2019S frequency in European countries and reaching frequency up to 41% in North African cases [20], while the second variation (G2385R) is common mainly in Asian populations [19, 21]. To date, apparent discrepancies between these variations have been reported, suggesting a more complicated phenotype in the G2385R mutation carriers than in LRRK2 G2019S mutation carriers [19].…”

Section: Introductionmentioning

confidence: 99%

DrosophilaMutant Model of Parkinson’s Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences

Rose

Corda

Solari

et al. 2016

Parkinson's Disease

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Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by the clinical triad: tremor, akinesia, and rigidity. Several studies have suggested that PD patients show disturbances in olfaction as one of the earliest, nonspecific nonmotor symptoms of disease onset. We sought to use the fruit fly Drosophila melanogaster as a model organism to explore olfactory function in LRRK loss-of-function mutants, which was previously demonstrated to be a useful model for PD. Surprisingly, our results showed that the LRRK mutant, compared to the wild flies, presents a dramatic increase in the amplitude of the electroantennogram responses and this is coupled with a higher number of olfactory sensilla. In spite of the above reported results, the behavioural response to olfactory stimuli in mutant flies is impaired compared to that obtained in wild type flies. Thus, behaviour modifications and morphofunctional changes in the olfaction of LRRK loss-of-function mutants might be used as an index to explore the progression of parkinsonism in this specific model, also with the aim of studying and developing new treatments.

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“…5,6 The distribution of LRRK2 variants differs significantly among genetically diverse populations. 4,[7][8][9][10][11] The most commonly reported LRRK2 mutation, G2019S, accounts for~41% of PD in North African Arab-Berbers,~31% in Ashkenazi Jews with familial PD2, and is underrepresented in the Asian PD population. 7,12 Haplotype linkage disequilibrium studies suggest a common founder effect in these populations.…”

Section: Lrrk2mentioning

confidence: 99%

Understanding the role of genetic variability in LRRK2 in Indian population

et al. 2018

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Background Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. Objectives To resolve the role of LRRK2 in the Indian population. Methods We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. Results We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild‐type, the kinase domain variant showed 4‐fold increase in the kinase activity. Conclusions Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society

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The association between the LRRK2 G2385R variant and the risk of Parkinson’s disease: a meta-analysis based on 23 case–control studies

Cited by 29 publications

References 45 publications

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions

DrosophilaMutant Model of Parkinson’s Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences

Understanding the role of genetic variability in LRRK2 in Indian population

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