LRRK2 Parkinson disease mutations enhance its microtubule association.
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ABSTRACT:
SUBMITTER: Kett LR
PROVIDER: S-EPMC3263991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n?=?97) and non-carriers (n?=?391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P?<?0.001), were more likely to be women (51.5% vs. 37.9%; P?=?0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P?<?0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P?<?0.001), postural instability and gait difficulty (PIGD) (P?=?0.043), and a persistent levodopa response for >5 years (P?=?0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
| S-EPMC3859844 | biostudies-literature
Project description:BackgroundMutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive.MethodsHuman neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2.ResultsHere, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a.ConclusionsOur findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects.
| S-EPMC5778812 | biostudies-literature
Project description:ImportanceDespite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.ObjectiveTo evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.Design, setting, and participantsThis longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.Main outcomes and measuresThe associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.ResultsAmong 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).Conclusions and relevanceThese findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
| S-EPMC8060834 | biostudies-literature
Project description:LRRK2 mutations are recognized as the most frequent genetic cause of both familial and sporadic parkinsonism identified to date. A remarkable feature of this form of parkinsonism is the variable penetrance of symptom manifestation resulting in a wide range of age-at-onset in patients. Herein we use a functional approach to identify the Lrrk1 protein as a potential disease modifier demonstrating an interaction and heterodimer formation with Lrrk2. In addition, evaluation of LRRK1 variants in our large Lrrk2 p.G2019S-parkinsonism series from a Tunisian (n=145) identified a missense mutation (p.L416M) resulting in an average 6.2 years younger age at disease onset. In conclusion we show that the interaction of Lrrk1-Lrrk2 can form protein dimers and this interaction may influence the age of symptomatic manifestation in Lrrk2-parkinsonism patients.
| S-EPMC2847049 | biostudies-literature
Project description:Mutations in the genes PRKN and LRRK2 are the most frequent known genetic lesions among Parkinson's disease patients. We have previously reported that in the Portuguese population the LRRK2 c.6055G > A; p.G2019S mutation has one of the highest frequencies in Europe.Here, we follow up on those results, screening not only LRRK2, but also PRKN, SNCA and PINK1 in a cohort of early-onset and late-onset familial Portuguese Parkinson disease patients. This series comprises 66 patients selected from a consecutive series of 132 patients. This selection was made in order to include only early onset patients (age at onset below 50 years) or late-onset patients with a positive family history (at least one affected relative). All genes were sequenced bi-directionally, and, additionally, SNCA, PRKN and PINK1 were subjected to gene dosage analysis.We found mutations both in LRRK2 and PRKN, while the remaining genes yielded no mutations. Seven of the studied patients showed pathogenic mutations, in homozygosity or compound heterozygosity for PRKN, and heterozygosity for LRRK2.Mutations are common in Portuguese patients with Parkinson's disease, and these results clearly have implications not only for the genetic diagnosis, but also for the genetic counseling of these patients.
| S-EPMC2248204 | biostudies-literature
Project description:Several genetic variations have been associated with Parkinson disease in different populations over the past few years. Although a considerable number of worldwide populations have been screened for these variants, results from Sub-Saharan populations are very scarce in the literature. In the present report we have screened a cohort of Parkinson disease patients (n = 57) and healthy controls (n = 51) from Nigeria for mutations in the genes PRKN, LRRK2 and ATXN3. No pathogenic mutations were found in any of the genes. Hence, common pathogenic mutations in these genes, observed in several different populations, are not a frequent cause of Parkinson disease in Nigeria.
| S-EPMC2559870 | biostudies-literature
Project description:Importance:Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. Objective:To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. Design, Setting, and Participants:A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. Main Outcomes and Measures:Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. Results:Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). Conclusions and Relevance:Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.
| S-EPMC5885854 | biostudies-literature
Project description:Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8, OMIM 607060) gene represent the most common known cause of hereditary Parkinson's disease (PD) with late-onset and dominant inheritance. LRRK2 protein is composed of multiple domains including two distinct enzymatic domains, a kinase and a Ras-of-complex (Roc) GTPase, connected by a C-terminal-of-Roc (COR) domain, and belongs to the ROCO protein family. Disease-causing mutations located in the kinase domain enhance kinase activity (i.e., G2019S) whereas mutations clustering within the Roc-COR tandem domain impair GTPase activity (i.e., R1441C/G and Y1699C). Familial LRRK2 mutations commonly induce neuronal toxicity that, at least for the frequent G2019S variant, is dependent on kinase activity. The contribution of GTPase activity to LRRK2-dependent neuronal toxicity is not yet clear. Therefore, both GTPase and kinase activity may be important for mediating neurodegeneration in PD due to familial LRRK2 mutations. At present, the physiological function of LRRK2 in the mammalian brain and the regulation of its enzymatic activity are incompletely understood. In this review, we focus on the GTPase domain of LRRK2 and discuss the recent advances in elucidating its function and its interplay with the kinase domain for the regulation of LRRK2 activity and toxicity. GTPase activity is an important feature of LRRK2 biology and pathophysiology and represents an underexplored yet potentially tractable therapeutic target for treating LRRK2-associated PD.
| S-EPMC3976973 | biostudies-literature
Project description:Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.
| S-EPMC4435452 | biostudies-literature
Project description:ObjectiveLeucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.MethodsWe identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.ResultsThe clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.ConclusionsThe distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.
| S-EPMC3906630 | biostudies-literature