LRRK2-related Parkinson's Disease Research Articles

Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.

Using Extracellular miRNA Signatures to Identify Patients with LRRK2-Related Parkinson's Disease.

Mutations in the Leucine Rich Repeat Kinase 2 gene are highly relevant in both sporadic and familial cases of Parkinson's disease. Specific therapies are entering clinical trials but patient stratification remains challenging. Dysregulated microRNA expression levels have been proposed as biomarker candidates in sporadic Parkinson's disease. In this proof-of concept study we evaluate the potential of extracellular miRNA signatures to identify LRRK2-driven molecular patterns in Parkinson's disease. We measured expression levels of 91 miRNAs via RT-qPCR in ten individuals with sporadic Parkinson's disease, ten LRRK2 mutation carriers and eleven healthy controls using both plasma and cerebrospinal fluid. We compared miRNA signatures using heatmaps and t-tests. Next, we applied group sorting algorithms and tested sensitivity and specificity of their group predictions. miR-29c-3p was differentially expressed between LRRK2 mutation carriers and sporadic cases, with miR-425-5p trending towards significance. Individuals clustered in principal component analysis along mutation status. Group affiliation was predicted with high accuracy in the prediction models (sensitivity up to 89%, specificity up to 70%). miRs-128-3p, 29c-3p, 223-3p, and 424-5p were identified as promising discriminators among all analyses. LRRK2 mutation status impacts the extracellular miRNA signature measured in plasma and separates mutation carriers from sporadic Parkinson's disease patients. Monitoring LRRK2 miRNA signatures could be an interesting approach to test drug efficacy of LRRK2-targeting therapies. In light of small sample size, the suggested approach needs to be validated in larger cohorts.

Cell-free mitochondrial DNA deletions in idiopathic, but not LRRK2, Parkinson's disease

Mitochondrial dysfunction happens in both idiopathic (iPD) and LRRK2-related Parkinson's disease (LRRK2-PD). Nonetheless, previous studies suggested that a different type of mitochondrial pathology underlies the neurodegeneration in these two disorders. To further explore this hypothesis, we developed a novel multiplex digital PCR assay that allows the absolute quantification of cell-free mitochondrial DNA (cf-mtDNA) copy number and deletion ratio directly in cerebrospinal fluid (CSF) by simultaneously measuring two opposed regions of the mtDNA circular molecule, one of them in the commonly deleted major arc. The results confirmed that the content of cf-mtDNA in CSF was statistically significantly different between iPD and LRRK2-PD patients. Moreover, we found high cf-mtDNA deletion levels in CSF from patients with iPD, but not LRRK2-PD. The high cf-mtDNA deletion frequency in iPD was validated in an independent cohort. These results indicated that the content and deletion ratio of cf-mtDNA may differentiate iPD from LRRK2-PD, and provides further evidence of the different mitochondrial pathophysiology between these two forms of the disease.

Modeling Parkinson's disease in LRRK2 mice: focus on synaptic dysfunction and the autophagy-lysosomal pathway.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with familial and sporadic forms of Parkinson's disease (PD), for which the LRRK2 locus itself represents a risk factor. Idiopathic and LRRK2-related PD share the main clinical and neuropathological features, thus animals harboring the most common LRRK2 mutations, i.e. G2019S and R1441C/G, have been generated to replicate the parkinsonian phenotype and investigate the underlying pathological mechanisms. Most LRRK2 rodent models, however, fail to show the main neuropathological hallmarks of the disease i.e. the degeneration of dopaminergic neurons in the substantia nigra pars compacta and presence of Lewy bodies or Lewy body-like aggregates of α-synuclein, lacking face validity. Rather, they manifest dysregulation in cellular pathways and functions that confer susceptibility to a variety of parkinsonian toxins/triggers and model the presymptomatic/premotor stages of the disease. Among such susceptibility factors, dysregulation of synaptic activity and proteostasis are evident in LRRK2 mutants. These abnormalities are also manifest in the PD brain and represent key events in the development and progression of the pathology. The present minireview covers recent articles (2018-2021) investigating the role of LRRK2 and LRRK2 mutants in the regulation of synaptic activity and autophagy-lysosomal pathway. These articles confirm a perturbation of synaptic vesicle endocytosis and glutamate release in LRRK2 mutants. Likewise, LRRK2 mutants show a marked impairment of selective forms of autophagy (i.e. mitophagy and chaperone-mediated autophagy) and lysosomal function, with minimal perturbations of nonselective autophagy. Thus, LRRK2 rodents might help understand the contribution of these pathways to PD.

Molecular Modeling Study on the Interaction Mechanism between the LRRK2 G2019S Mutant and Type I Inhibitors by Integrating Molecular Dynamics Simulation, Binding Free Energy Calculations, and Pharmacophore Modeling.

Leucine-rich repeat kinase 2 (LRRK2) has been reported in the pathogenesis of Parkinson's disease (PD). G2019S mutant is the most common pathogenic mutation in LRRK2-related PD patients. Inhibition of LRRK2 kinase activity is proposed to be a new therapeutic approach for PD treatment. Therefore, understanding the molecular basis of the interaction between LRRK2 and its inhibitors will be valuable for the discovery and design of LRRK2 inhibitors. However, the structure of human LRRK2 in complex with the inhibitor has not been determined, and the inhibitory mechanism underlying LRRK2 still needs to be further investigated. In this study, molecular dynamics (MD) simulation combined with the molecular mechanics generalized born surface area (MM-GBSA) binding free energy calculation and pharmacophore modeling methods was employed to explore the critical residues in LRRK2 for binding of inhibitors and to investigate the general structural features of the inhibitors with diverse scaffolds. The results from MD simulations suggest that the hinge region residues Glu1948 and Ala1950 play a significant role in maintaining the intermolecular hydrogen bond interaction with the G2019S LRRK2 protein and inhibitor. The strong hinge hydrogen bond with an occupancy rate of more than 95% represents the high activity of LRRK2 inhibitors, and the hydrogen bond interaction with the kinase catalytic loop region could compromise selectivity. Further pharmacophore modeling reveals that the high activity LRRK2 inhibitor should have one aromatic ring, one hydrogen bond acceptor, and one hydrogen bond donor. Hence, the obtained results can provide valuable information to understand the interactions of LRRK2 inhibitors at the atomic level that will be helpful in designing potent inhibitors of LRRK2.

LRRK2 Loss-of-Function Variants: When Less Is More.

Gain-of-function variants in leucine-rich repeat kinase 2 (LRRK2) are the most common monogenic cause of Parkinson's disease (PD), albeit with incomplete penetrance, indicating that reduction of LRRK2 kinase activity is a reasonable therapeutic strategy for LRRK2-related PD.1 However, LRRK2 inhibition in animal models was associated with abnormal phenotypes in the lung, kidney, and liver, thus raising safety concerns.2 Resources such as the Genome Aggregation Database or UK Biobank, built on large-scale sequencing projects, represent compelling tools for assessing genetic variant frequency. These were employed by Whiffin and colleagues3 to investigate the frequency of LRRK2 loss-of-function (LoF) variants in humans and their association with specific phenotypes. Among 187,518 individuals in the 2 aforementioned cohorts, they identified 352 carriers of heterozygous LRRK2 LoF variants, implying that approximately 1 in 500 humans harbors such a variant.3 Using genotyping data from the personal genetics company 23andMe, Whiffin and colleagues3 identified an additional 1,103 individuals with LRRK2 LoF variants.3 No reduction in lifespan or overrepresentation of any phenotype affecting the lung, liver, kidney, cardiovascular system, nervous system, immunity, or cancer in carriers of LRRK2 LoF variants was observed.3 In an earlier study, heterozygous LRRK2 LoF variants were identified at comparable percentages of clinically diagnosed patients with PD and controls, suggesting a lack of association between the partial loss of LRRK2 and PD.4 These results collectively suggest that an endogenous decrease of LRRK2 levels and consequently of its activity does not seem to elicit highly penetrant phenotypes, although to date LRRK2 LoF variants have never been investigated specifically in cohorts of patients with unexplained severe manifestations (including those seen in animal models upon LRRK2 inhibition). Thus, the therapeutic administration of compounds intended to decrease LRRK2 enzymatic activity (kinase inhibitors) or levels (antisense oligonucleotides) is not expected to cause harmful effects. Currently, 3 LRRK2-targeted compounds are being tested in phase 1 or 1b clinical trials: the LRRK2 kinase inhibitors DNL151 and DNL201 from Denali Therapeutics Inc., (San Francisco, CA, USA) and the antisense oligonucleotide BIIB094 from Biogen.3 As a caveat, a coinciding loss of both LRRK2 and its functional homolog LRRK1 results in earlier mortality, a loss of dopaminergic neurons, and an increase in α-synuclein in a double-knockout mouse model.5 Hence, targeting LRRK2 may not be safe in individuals with LRRK1 homozygous or heterozygous LoF variants. While it may thus be advisable to exclude the presence of such variants by genetic testing of LRRK1 in individuals prior to the administration of any LRRK2-directed treatment, LRRK2 inhibition is a promising and potentially safe new therapeutic strategy. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the first draft, B. Review and Critique. T.U.: 1A, 1B,1C,2A,2B A.W.:1A,1B,1C,2A,2B T.U. reports the following: employment with University Medical Center Schleswig-Holstein, Campus Lübeck, Germany. A.W. is an advisor for medical writing at CENTOGENE GmbH and reports employment with University Medical Center Schleswig-Holstein, Campus Lübeck, Germany; honoraria from CENTOGENE GmbH; and a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft) Research Unit (FOR2488).

LRRK2-Related Parkinson's Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis.

Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials. Although the precise pathophysiological functions of LRRK2 remain largely unknown, PD-associated mutants have been shown to alter various intracellular vesicular trafficking pathways, especially those related to endolysosomal protein degradation events. In addition, biochemical studies have identified a subset of Rab proteins, small GTPases required for all vesicular trafficking steps, as substrate proteins for the LRRK2 kinase activity in vitro and in vivo. Therefore, it is crucial to evaluate the impact of such phosphorylation on neurodegenerative mechanisms underlying LRRK2-related PD, especially with respect to deregulated Rab-mediated endolysosomal membrane trafficking and protein degradation events. Surprisingly, a significant proportion of PD patients due to LRRK2 mutations display neuronal cell loss in the substantia nigra pars compacta in the absence of any apparent α-synuclein-containing Lewy body neuropathology. These findings suggest that endolysosomal alterations mediated by pathogenic LRRK2 per se are not sufficient to cause α-synuclein aggregation. Here, we will review current knowledge about the link between pathogenic LRRK2, Rab protein phosphorylation and endolysosomal trafficking alterations, and we will propose a testable working model whereby LRRK2-related PD may present with variable LB pathology.

Four-Year Longitudinal Study of Motor and Non-motor Symptoms in LRRK2-Related Parkinson's Disease.

Objectives: In a prospective 4-year study, we evaluated the progression of motor and non-motor symptoms in Parkinson's disease (PD) patients with Asian-specific LRRK2 risk variants and non-carriers.Methods: A total of 202 patients with PD, including 133 risk variant carriers and 69 non-carriers, were followed up and evaluated using the Modified Hoehn and Yahr staging scale, Unified Parkinson's Disease Rating Scale part III, Non-motor Symptom Scale, Parkinson's disease Questionnaire-39 item version. Means of generalized estimating equation model was performed to compare the differences from baseline between LRRK2 risk variant carriers and non-carriers.Results: Our longitudinal analysis revealed that risk variant carriers exhibited greater progression than non-carriers after 4 years based on the modified Hoehn and Yahr staging scale (risk variants carriers, 0.65; non-carriers, 0.06; P = 0.041). Meanwhile, Unified Parkinson's Disease Rating Scale gait and posture score in risk variant carriers also showed greater increase than that in non-carriers, although the difference was not statistically significant. Non-carriers experienced a transient improvement in non-motor symptoms at the early stage of PD, as scores at visit two significantly reduced compared to baseline in Non-motor Symptom Scale domain 3 (mood/apathy), Parkinson's disease Questionnaire-39 item version domain 3 (emotional well-being), and frequency of NMS in non-carriers but not in risk variants carriers.Conclusions: PD gene risk variant carriers were more likely to progress faster in their motor severity than non-carriers. There were transient differences in certain non-motor symptoms and quality of life in carriers. However, more studies are warranted to assess the association of PD risk variants and progression of non-motor symptoms.

SNCA but not DNM3 and GAK modifies age at onset of LRRK2-related Parkinson's disease in Chinese population.

Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD. In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers. The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282. Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.

Clinical Heterogeneity Among LRRK2 Variants in Parkinson's Disease: A Meta-Analysis.

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Variants in the LRRK2 gene have been shown to be associated with PD. However, the clinical characteristics of LRRK2-related PD are heterogeneous. In our study, we performed a comprehensive pooled analysis of the association between specific LRRK2 variants and clinical features of PD.Methods: Articles from the Medline, Embase, and Cochrane databases were included in the meta-analysis. Strict inclusion criteria were applied, and detailed information was extracted from the final original articles included. Revman 5.3 software was used for publication biases and pooled and sensitivity analyses.Results: In all, 66 studies having the clinical manifestations of PD patients with G2019S, G2385R, R1628P, and R1441G were included for the final analysis. The prominent clinical features of LRRK2-G2019S-related PD patients were female sex, higher rates of early-onset PD (EOPD), and family history (OR: 0.77 [male], 1.37, 2.62; p < 0.00001, 0.02, < 0.00001). PD patients with G2019S were more likely to have high scores of Schwab & England (MD: 1.49; p < 0.00001), low GDS scores, high UPSIT scores (MD: 0.43, 4.70; p = 0.01, < 0.00001), and good response to L-dopa (OR: 2.33; p < 0.0001). Further, G2019S carriers had higher LEDD (MD: 115.20; p < 0.00001) and were more likely to develop motor complications, such as dyskinesia and motor fluctuations (OR: 2.18, 2.02; p < 0.00001, 0.04) than non-carriers. G2385R carriers were more likely to have family history (OR: 2.10; p = 0.007) than non-G2385R carriers and lower H-Y and higher MMSE scores (MD: −0.13, 1.02; p = 0.02, 0.0007). G2385R carriers had higher LEDD and tended to develop motor complications, such as motor fluctuations (MD: 53.22, OR: 3.17; p = 0.01, < 0.00001) than non-carriers. Other clinical presentations did not feature G2019S or G2385R. We observed no distinct clinical features for R1628P or R1441G. Our subgroup analyses in different ethnic group for specific variant also presented with relevant clinical characteristics of PD patients.Conclusions: Clinical heterogeneity was observed among LRRK2-associated PD in different variants in total and in different ethnic groups, especially for G2019S and G2385R.

Cognitive profile and 18F-fluorodeoxyglucose PET study in LRRK2-related Parkinson's disease

IntroductionLRRK2 gene mutations underlie the most common mendelian form of Parkinson's Disease (PD), designated PARK8, that shows clinical features similar to those in idiopathic PD (IPD). We assessed the cognitive functions and the cerebral metabolism measured with 18F-fluorodeoxyglucose (FDG)-PET in PARK8 patients compared with IPD. Patients and methodsWe enrolled eight PARK8 patients and eight IPD patients, comparable for onset age, stage, severity and duration of disease. Mean age ± SD was 61.8 ± 10.9 years and disease duration 8.4 ± 5.8 in PARK8, and 61.4 ± 14.7 and 7.0 ± 4.8 in IPD. All subjects underwent a wide neuropsychological assessment and a FDG-PET. Cerebral regional relative metabolic maps were evaluated using voxel-based analysis with statistical parametric mapping. ResultsMotor and non-motor phenotype and neuropsychological evaluation did not differ between PARK8 and IPD. We detected one case of dementia and four of Mild Cognitive Impairment in each group. At FDG-PET, compared to controls, IPD patients revealed a significant relative posterior cortical hypometabolism in the left temporal and inferior parietal and in the right inferior and superior parietal regions, whereas patients with LRRK2 mutation, at a less conservative threshold, showed only a relative left inferior parietal hypometabolism. No differences were found between patients with PARK8 and IPD. ConclusionsThe results confirm a comparable cognitive profile between LRRK2 and IPD patients. FDG-PET study showed a pattern of posterior cortical hypometabolism in both groups, although less severe in LRRK2-related PD. The milder decrease of cortical metabolism in PARK8 might be due to a less marked pathological involvement compared to IPD.

Mitochondrial DNA in CSF distinguishes LRRK2 from idiopathic Parkinson's disease

Mitochondrial DNA regulates mitochondrial function which is altered in both idiopathic and familial forms of Parkinson's disease. To investigate whether these two disease forms exhibit an altered regulation of mitochondrial DNA we measured cell free mitochondrial DNA content in cerebrospinal fluid (CSF) from idiopathic and LRRK2-related Parkinson's disease patients. The concentration of mitochondrial DNA was measured using a digital droplet polymerase chain reaction technique in a total of 98 CSF samples from a cohort of subjects including: 20 LRRK2G2019S mutation carriers with Parkinson's disease, 26 asymptomatic LRRK2G2019S mutation carriers, 31 patients with idiopathic Parkinson's disease and 21 first-degree relatives of LRRK2 Parkinson's disease patients without the mutation. Here we report that LRRK2G2019S mutation carriers with Parkinson's disease exhibit a high concentration of mitochondrial DNA in CSF compared with asymptomatic LRRK2G2019S mutation carriers and with idiopathic Parkinson's disease patients. In addition, idiopathic, but not LRRK2 Parkinson's disease is associated with low CSF concentration of α-synuclein. These results show that high mitochondrial DNA content in CSF distinguishes idiopathic from LRRK2-related Parkinson's disease suggesting that different biochemical pathways underlie neurodegeneration in these two disorders.

The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research.

In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system.

The leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is one of the most common genetic causes in Parkinson's disease (PD). The penetrance of G2019S LRRK2 is incomplete and is age-dependent, therefore, it has been speculated that environmental toxins and aging could contribute to G2019S LRRK2-related PD pathogenesis. To prove this speculation, we performed a longitudinal investigation in mice bearing G2019S LRRK2 mutation. BAC G2019S LRRK2 transgenic (Tg) mice and their wildtype (Wt) littermates were treated with lactacystin, a specific proteasome inhibitor. The susceptibilities of mice to lactacystin-induced nigrostriatal dopaminergic (DAergic) degeneration were evaluated, at 5 and 12 months of age. We found that lactacystin treatment caused a greater decline of striatal DA content in the Tg mice at either 5 or 12 months of age than their age-matched Wt littermates. Moreover, the lactacystin-treated Tg or Wt mice at 12 months of age lose much more nigral tyrosine hydroxylase (TH)-positive neurons than the mice at 5 months of age, indicating an age-associated DAergic neurotoxicity. Additionally, stereotactic injection of lactacystin induced a dramatic increase of activated microglia in substantia nigra of mice at 12 months of age, compared with mice at 5 months of age. In summary, our study suggests that expression of the G2019S mutation in the mouse LRRK2 gene confers an age-associated high susceptibility to proteasome inhibition-induced nigrostriatal DAergic degeneration.

Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD.

Cognitive profile of LRRK2-related Parkinson's disease.

Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized. A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models. LRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03). Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society.

Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD. We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs. To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

Motor phenotype of LRRK2-associated Parkinson's disease: a Tunisian longitudinal study.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) were found to be a significant cause of late-onset autosomal dominant forms of Parkinson's disease (PD). To determine the motor characteristics of LRRK2-related disease, we conducted a longitudinal study of 58 G2019S LRRK2-associated PD patients and compared them with genetically undefined (GU) PD patients. Fifty-eight patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared with 54 sporadic PD patients with negative tests for LRRK2 G2019S, PINK1, SNCA, PRKN, and DJ1 mutations. Patients were assessed at baseline and after a follow-up period of 6 years. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Hoehn and Yahr, and the Schwab and England scores were determined. Logistic regression was used to examine associations of G2019S mutation status with motor phenotype and rate of motor decline. The LRRK2-associated PD patients had a mean age of onset of 56.25 ± 12.05 years and in most cases (58.6%) a postural instability gait difficulty (PIGD) phenotype. The mean annual decline in the MDS-UDRS III motor score and the Hoehn and Yahr staging was of 1.3% and 2%, respectively. The PIGD phenotype predicted a more rapid progression of motor impairment. The PD motor phenotype and motor scores were similar in the LRRK2-associated PD group and in the GU PD group, with no significant differences in the progression rate of motor impairment. Motor phenotype seems to be similar in LRRK2-related PD and idiopathic PD.

Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications.

Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

LRRK2 phosphorylates novel tau epitopes and promotes tauopathy

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1188-4) contains supplementary material, which is available to authorized users.