Leucine-rich Repeat Kinase 2 R1628P Research Articles

Connectivity of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P carriers.

Neuroimaging studies have shown that the functional connectivity (FC) of corticostriatal circuits in nonmanifesting leucine-rich repeat kinase 2 (LRRK2) G2019S mutation carriers mirrors neural changes in idiopathic Parkinson's disease (PD). In contrast, neural network changes in LRRK2 G2385R and R1628P mutations are unclear. We aimed to investigate the FC of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P mutation carriers (NMCs). Twenty-three NMCs, 28 PD patients, and 29 nonmanifesting noncarriers (NMNCs) were recruited. LRRK2 mutation analysis was performed on all participants. Clinical evaluation included MDS-UPDRS. When compared to NMNCs, NMCs showed significantly reduced FC between the caudate nucleus and superior frontal gyrus and cerebellum, and between the nucleus accumbens and parahippocampal gyrus, amygdala, and insula. We also found increased striatum-cortical FC in NMCs. Although the corticostriatal circuits have characteristic changes similar to PD, the relatively intact function of the sensorimotor striatum-cortical loop may result in less possibility of developing parkinsonian motor symptoms for the NMCs. This study helps explain why LRRK2 G2385R and R1628P mutations are risk factors rather than pathogenic mutations for PD and suggests that various LRRK2 mutations have distinct effects on neural networks.

Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson's disease

IntroductionGlucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinson's disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants. MethodsThe participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender. ResultsTotal 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers. ConclusionsThe prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD.

Association of LRRK2 R1628P variant with Parkinson's disease in Ethnic Han-Chinese and subgroup population.

Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson’s disease (PD). The R1628P variant of LRRK2 may be a specific risk factor for PD in ethnic Han-Chinese populations. This study is to elucidate the epidemiological feature of R1628P in ethnic Han-Chinese population with PD. A comprehensive meta-analysis was performed to evaluate the precise association between R1628P variant and the risk for PD in ethnic Han-Chinese and subgroups stratified by gender, onset age, or family history. The analysis assessing the role of R1628P on the risk of PD in ethnic Han-Chinese supported a significant association, and the odds ratio was 1.86. We further estimate the specific prevalence in relevant ethnic Han-Chinese subgroups. After stratifying the eligible data by gender, onset age, or family history, significant associations were found in all male, female, early-onset, late-onset, familial and sporadic subgroups, and the odds ratio were 1.90, 1.94, 2.12, 1.75, 6.71 and 1.81 respectively. In conclusion, our meta-analysis suggests that R1628P variant of LRRK2 has a significant association with the risk of PD in ethnic Han-Chinese and subgroup population.

Relationship between LRRK2 R1628P polymorphism and Parkinson's disease in Asian populations

Although the leucine-rich repeat kinase 2 (LRRK2) R1628P polymorphism has been associated with the risk of Parkinson's disease (PD) in Taiwan, China, and Singapore, there are conflicting findings regarding this relationship. Thus, the aim of the present meta-analysis was to evaluate the associations between the LRRK2 R1628P polymorphism (rs33949390) and PD in Asian populations. A search for eligible studies was performed in PubMed, Embase, SinoMed, and the China Knowledge Resource Integrated Database, and pooled odds ratios and 95% confidence intervals were used to evaluate the strength of the association between the R1628P polymorphism and PD. This meta-analysis assessed 19 studies from 14 papers that involved a total of 9,927 PD patients and 8,602 controls and found that the R1628P polymorphism was significantly associated with the risk of PD in Asian populations. Moreover, stratification analyses indicated that the R1628P polymorphism was significantly associated with an increased risk of PD among Chinese as well as non-Chinese Asian populations and an increased risk of PD in Chinese patients from China, Taiwan, and Singapore. In a stratified analysis conducted according to age, significant associations were found for both late-onset PD and early-onset PD. The present data indicate that the R1628P polymorphism of the LRRK2 gene contributes to PD susceptibility in Asian, especially Chinese, populations.

The association between the LRRK2 R1628P variant and the risk of Parkinson’s disease in Asian: a meta-analysis

Many published case-control studies have investigated the association between Leucine-rich repeat kinase 2(LRRK2) R1628P and the susceptibility of Parkinson’s disease (PD). However, controversial results were obtained. Herein we performed this meta-analysis to assess the association between the LRRK2 R1628P variants and the risk of PD. Up to January of 2016, 5 databases were searched to identify case-control studies involving LRRK2 R1628P variants and PD risk. A total of 5736 PD patients and 4786 controls in 14 case-control studies were included in this meta-analysis. And STATA 12.0 statistics software was used to calculate available data from each study. The pooled odds ratios (OR) and 95% confidence interval (CI) were calculated to assess the genetic association between LRRK2 R1628P polymorphism and the risk of PD. The results indicated that LRRK2 R1628P variants were increased risk of PD when all studies were pooled (C vs. G OR=1.983, 95% CI 1.640-2.399; GC+CC vs. GG OR=1.971, 95% CI 1.625–2.391). Moreover, in the subgroup analysis by ethnicity, increased risks were identified among Chinese (GC+CC vs. GG, OR=1.96, 95% CI 1.60–2.41) as well as in non-Chinese Asian races (GC+CC vs. GG, OR=2.03, 95% CI 1.13–3.65). Therefore, our results suggest that the C allele, GC and CC genotype of LRRK2 R1628P variants contribute to the susceptibility of PD in Asian.

Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity

BackgroundRecent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson’s disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.Principle FindingsUnlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn’t alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.ConclusionOur data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.

Lrrk2 R1628P variant is a risk factor for essential tremor.

Essential tremor (ET) and Parkinson's disease (PD) are two of the most common adult onset movement disorders with overlapping clinical features. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present initially with an ET phenotype. To address the possibility of a common genetic link between ET and PD, we examined the association between a common LRRK2 R1628P gene variant and ET. The LRRK2 R1628P was genotyped in ET cases and matched healthy controls. A total of 1277 subjects comprising of 450 ET cases and 827 controls were included. There were 40 heterozygote (GG to CG) variant out of 450 ET cases (genotypic frequency 8.9%) and 36 heterozygote variant (GG to CG, genotypic frequency 4.3%) and one homozygote variant (GG to CC) out of 827 controls. Subjects carrying the R1628P variant had a twofold increased risk of ET (p = 0.0035, OR = 2.20 and 95% confidence interval is 1.30–3.73). Using a case control methodology, we demonstrated an association between a known PD risk variant, LRRK2 R1628P, with ET. Subjects carrying the R1628P variant had twice the risk of developing ET. The sharing of a similar gene risk variant suggests a possible pathophysiologic link between PD and ET.

Non-motor symptoms in Chinese Parkinson's disease patients with and without LRRK2 G2385R and R1628P variants.

Non-motor symptoms (NMS) are common among patients with Parkinson's disease (PD). However, reports on NMS in Chinese PD population are scarce. Little is known about NMS in patients with Asian specific leucine-rich repeat kinase 2 (LRRK2) variants in G2385R and R1628P. This study aimed to elucidate the clinical characteristics of NMS in Chinese PD patients and to ascertain if there were differences in NMS between PD patients with and without LRRK2 variants. A multicenter, observational study was conducted with 1,225 sporadic PD (sPD) patients recruited from a PD cohort of the Chinese National Consortium on neurodegenerative diseases, 163 participants had the LRRK2 variants. The Non-motor Symptom Questionnaire (NMSQ) was used to screen for the presence of NMS. This study found the majority of sPD patients (97.6%) had at least one NMS. A mean of 8.72 NMS (SD=5.43) was reported per patient. Forgetfulness, constipation and daytime sleepiness were found to be the most frequent NMS. Moreover, the number of NMS was positively correlated with the age, disease duration, Hoehn & Yahr stage and the motor scores of the unified Parkinson's disease rating scale. Although no discrepancy was found in the number of NMS between sPD patients with and without LRRK2 variants, nocturia was less common in LRRK2 variants carriers than in non-carriers (P=0.045). NMS appear to be prevalent in Chinese sPD population. There are no differences in the NMS phenotype between LRRK2 and no LRRK2 patients.

The LRRK2 R1628P Variant Plays a Protective Role in Han Chinese Population with Alzheimer's Disease

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative disorders that may share some overlapping etiologies. Mutations within leucine-rich repeat kinase 2 (LRRK2) have been reported to be responsible for PD, and the location of LRRK2 is within a linkage peak for sporadic AD (SAD). The aim of this study was to investigate two Asian-specific LRRK2 variants, R1628P and G2385R, with the association of Han Chinese SAD. Genotyping of R1628P and G2385R was performed by PCR-restriction fragment length polymorphism (RFLP) analysis in 390 patients with SAD and 545 unrelated age- and sex-matched healthy controls. The frequency of the C allele within R1628P was more than three times higher in control group (1.7%) than in patients with SAD (0.5%) (OR 0.264; 95% CI, 0.088-0.792, P = 0.018). After stratification by the presence of one or two apolipoprotein E ε4 alleles, the protective effect becomes stronger (ε44: OR 0.028; 95% CI, 0.003-0.303, P = 0.003; ε4: OR 0.104; 95% CI, 0.013-0.818, P = 0.031). However, no difference was found in G2385R variant. Our study suggested that R1628P variant within LRRK2 plays a protective role in Han Chinese population with SAD and such effect has an interaction with the APOE genotype.

LRRK2 variant associated with Alzheimer's disease

Overlapping neurodegenerative pathologies (including Alzheimer's disease, AD) have been described in Parkinson's disease (PD) patients with leucine-rich repeat kinase-2 (LRRK2) mutations. We analyzed a LRRK2 PD (R1628P) risk variant in a group of 885 subjects comprising of AD and controls. The frequency of the R1628P allele was higher in AD compared to controls (3.5% vs. 1.6%, OR 2.3, 95 CI 1.2-4.4, p=0.018). In vitro, the mean percentage of apoptosis and cell death observed for the R1628P transfected human cell lines was higher compared to wild type 21.8 ± 1.9, vs. 17.1 ± 1.3, p<0.05, 30.2 ± 2.2 vs. 25.7 ± 1.3, p<0.05). The LRRK2 R1628P variant increases the risk of AD in our population and our in vitro findings suggest that it is a functional variant and predisposes to apoptosis.

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han‐Chinese from mainland China

Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han-Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60-6.17, P < 0.01]. Considering the age at onset, this difference was found only in late-onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90-7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han-Chinese population.

LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China

Common genetic variants that increase the risk for Parkinson's disease (PD) may differentiate patient subgroups and influence future individual therapeutic strategies. Previous studies have found associations between PD and polymorphisms located within the leucine-rich repeat kinase 2 ( LRRK2) gene in ethnic Han Chinese from Taiwan and Singapore. Herein, we performed a case-control study and provide evidence supporting the LRRK2 R1628P variant as a risk factor for PD in 2 separate Chinese Han populations from mainland China. A total of 328 PD patients and 300 control individuals were genotyped using PCR-restriction fragment length polymorphism analysis. Differences in genotype frequencies between groups were assessed by the chi-square test. In the PD group, 17 patients (5.2%) were heterozygous for the R1628P variant. This was significantly higher than for the control group [2.0%, P < 0.05].No one carrier of the LRRK2 G2385R variant was detected in all the carriers of the R1628P variant. Our results confirm that the LRRK2 R1628P variant contributes to the pathogenesis of PD in Chinese Han populations.