LRRK2-associated Parkinson's Disease Research Articles

Analysis of retinal nerve layers in idiopathic, LRRK2-associated Parkinson's disease and unaffected carriers of G2019S mutation

IntroductionIn both prodromal and early symptomatic stages of idiopathic PD (iPD) peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thinning have been identified. Here we assessed whether these alterations can also be detected in symptomatic and presymptomatic stages of LRRK2-PD. Methods218 eyes belonging to 20 iPD, 19 LRRK2-PD (L2PD), 24 LRRK2 non-manifesting carriers (L2NMC), and 46 controls (HCs). pRNFL, mGCL thickness (squares), and Bruch's membrane opening minimum rim width were evaluated by SD-OCT. In L2NMC, 123I-ioflupane SPECT (DaT-SPECT) with semi-quantitative analysis was carried out. ResultsCompared to HCs, iPD patients showed significant thinning of the temporal (BMO-MRW and pRNFL), superior-temporal (BMO-MRW), inferior-temporal (BMO-MRW), superior-nasal (BMO-MRW) and central sectors (BMO-MRW) (p < 0.05), as well as in five mGCL sectors (p < 0.05). No significant differences were found between the L2PD or L2NMC and HCs. BMO-MRW thickness in its temporal-superior, superior-nasal and middle sectors was influenced by disease duration (p < 0.05) and mGCL thickness in sectors TS1, TS2, TS3, NS1 and NS3 was influenced by UPDRSIII and age (p < 0.05). ConclusionLRRK2-PD is distinguished from iPD by absent or less retinal nerve involvement, both in clinical and preclinical stages.

Increased Phospho-AKT in Blood Cells from LRRK2 G2019S Mutation Carriers.

The purpose of this study was to investigate whether differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed phospho(P)-Ser-935-LRRK2 and P-Ser-473-AKT levels in peripheral blood cells from patients with G2019S LRRK2-associated PD (L2PD, n=31), G2019S LRRK2 non-manifesting carriers (L2NMC, n=26), idiopathic PD (iPD, n=25), and controls (n=40, total n=122). We found no differences at P-Ser-935-LRRK2 between groups but detected a specific increase of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD. Although insensitive to LRRK2 inhibition, our study identifies P-Ser-473-AKT as an endogenous candidate biomarker for peripheral inflammation in G2019S carriers using accessible blood cells. ANN NEUROL 2022;92:888-894.

Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease.

Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.

Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

Differential Phospho-Signatures in Blood Cells Identify LRRK2 G2019S Carriers in Parkinson's Disease.

BackgroundThe clinicopathological phenotype of G2019S LRRK2‐associated Parkinson's disease (L2PD) is similar to idiopathic Parkinson's disease (iPD), and G2019S LRRK2 nonmanifesting carriers (L2NMCs) are at increased risk for development of PD. With various therapeutic strategies in the clinical and preclinical pipeline, there is an urgent need to identify biomarkers that can aid early diagnosis and patient enrichment for ongoing and future LRRK2‐targeted trials.ObjectiveThe objective of this work was to investigate differential protein and phospho‐protein changes related to G2019S mutant LRRK2 in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify specific phospho‐protein changes associated with the G2019S mutation and with disease status, and compare findings with patients with iPD.MethodsWe performed an unbiased phospho‐proteomic study by isobaric label–based mass spectrometry using peripheral blood mononuclear cell group pools from a LRRK2 cohort from Spain encompassing patients with G2019S L2PD (n = 20), G2019S L2NMCs (n = 20), healthy control subjects (n = 30), patients with iPD (n = 15), patients with R1441G L2PD (n = 5), and R1441G L2NMCs (n = 3) (total N = 93).ResultsComparing G2019S carriers with healthy controls, we identified phospho‐protein changes associated with the G2019S mutation. Moreover, we uncovered a specific G2019S phospho‐signature that changes with disease status and can discriminate patients with G2019S L2PD, G2019S L2NMCs, and healthy controls. Although patients with iPD showed a differential phospho‐proteomic profile, biological enrichment analyses revealed similar changes in deregulated pathways across the three groups.ConclusionsWe found a differential phospho‐signature associated with LRRK2 G2019S for which, consistent with disease status, the phospho‐profile from PD at‐risk G2019S L2NMCs was more similar to healthy controls than patients with G2019S L2PD with the manifested disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

LRRK2 protein is expressed prominently in immune cells, cell types whose contribution to LRRK2-associated genetic Parkinson's disease (PD) is increasingly being recognised. We investigated the effect of inflammatory stimuli using RAW264.7 murine macrophage cells as model systems. A detailed time course of TLR2 and TLR4 stimulation was investigated through measuring LRRK2 phosphorylation at its specific phospho-sites, and Rab8 and Rab10 phosphorylation together with cytokine release following treatment with LPS and zymosan. LRRK2 phosphorylation at Ser935, Ser955 and Ser973 was increased significantly over untreated conditions at 4–24h in both WT-LRRK2 and T1348N-LRRK2 cell lines to similar extents although levels of Ser910 phosphorylation were maintained at higher levels throughout. Importantly we demonstrate that LPS stimulation significantly decreased phospho-Rab10 but not phospho-Rab8 levels over 4–24h in both WT-LRRK2 and T1348N-LRRK2 cell lines. The dephosphorylation of Rab10 was not attributed to its specific phosphatase, PPM1H as the levels remained unaltered with LPS treatment. MAPK phosphorylation occurred prior to LRRK2 phosphorylation which was validated by blocking TLR4 and TLR2 receptors with TAK242 or Sparstolonin B respectively. A significant decrease in basal level of TNFα release was noted in both T1348N-LRRK2 and KO-LRRK2 cell lines at 48h compared to WT-LRRK2 cell line, however LPS and zymosan treatment did not cause any significant alteration in the TNFα and IL-6 release between the three cell lines. In contrast, LPS and zymosan caused significantly lower IL-10 release in T1348N-LRRK2 and KO-LRRK2 cell lines. A significant decrease in phospho-Rab10 levels was also confirmed in human IPS-derived macrophages with TLR4 activation. Our data demonstrates for the first time that LRRK2-dependent Rab10 phosphorylation is modulated by LPS stimulation, and that cytokine release may be influenced by the status of LRRK2. These data provide further insights into the function of LRRK2 in immune response, and has relevance for understanding cellular dysfunctions when developing LRRK2-based inhibitors for clinical treatment.

Evolución y tratamiento de la fase avanzada de una serie de pacientes con enfermedad de Parkinson LRRK2

IntroductionLRRK2 mutations have traditionally been associated with a benign phenotype of Parkinson's disease (PD). Favourable responses to deep brain stimulation (DBS) are reported in the advanced phase. MethodsWe performed a retrospective analysis of the clinical characteristics and progression of 13 patients with LRRK2-associated PD (13 with G2019S and one with I1371 V). Nine patients were in the advanced phase, with a mean progression time of 7.2 years before reaching this phase. ResultsSeven patients underwent bilateral subthalamic DBS implantation, and two received infusion treatment. Patients with mutation G2019S responded excellently to DBS, with Unified Parkinson's disease rating scale (UPDRS) II and III scores improving by 80% at six months. This response was sustained over time. The patient with mutation I1371 V had a severe phenotype of the disease, and presented a moderate response to DBS. Patients with advanced LRRK2-associated PD showed predominantly frontal cognitive involvement, with significant language impairment. ConclusionsIn these patients, progression was faster in the advanced stage of the disease. We emphasise the suitability of subthalamic DBS in the management of these patients.

Mitochondrial Mechanisms of LRRK2 G2019S Penetrance.

Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson's disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is regulated by autophosphorylation. Yet, the penetrance of this gain-of-function mutation is incomplete, and thus far, few factors have been correlated with disease status in carriers. This includes (i) LRRK2 autophosphorylation in urinary exosomes, (ii) serum levels of the antioxidant urate, and (iii) abundance of mitochondrial DNA (mtDNA) transcription-associated 7S DNA. In light of a mechanistic link between LRRK2 kinase activity and mtDNA lesion formation, we previously investigated mtDNA integrity in fibroblasts from manifesting (LRRK2+/PD+) and non-manifesting carriers (LRRK2+/PD−) of the G2019S mutation as well as from aged-matched controls. In our published study, mtDNA major arc deletions correlated with PD status, with manifesting carriers presenting the highest levels. In keeping with these findings, we now further explored mitochondrial features in fibroblasts derived from LRRK2+/PD+ (n = 10), LRRK2+/PD− (n = 21), and control (n = 10) individuals. In agreement with an accumulation of mtDNA major arc deletions, we also detected reduced NADH dehydrogenase activity in the LRRK2+/PD+ group. Moreover, in affected G2019S carriers, we observed elevated mitochondrial mass and mtDNA copy numbers as well as increased expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates antioxidant signaling. Taken together, these results implicate mtDNA dyshomeostasis—possibly as a consequence of impaired mitophagy—in the penetrance of LRRK2-associated PD. Our findings are a step forward in the pursuit of unveiling markers that will allow monitoring of disease progression of LRRK2 mutation carriers.

Progress in LRRK2-Associated Parkinson's Disease Animal Models.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson’s disease (PD). Several genetic manipulations of the LRRK2 gene have been developed in animal models such as rodents, Drosophila, Caenorhabditis elegans, and zebrafish. These models can help us further understand the biological function and derive potential pathological mechanisms for LRRK2. Here we discuss common phenotypic themes found in LRRK2-associated PD animal models, highlight several issues that should be addressed in future models, and discuss emerging areas to guide their future development.

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

LRRK2 in Parkinson disease: challenges of clinical trials.

One of the most common monogenic forms of Parkinson disease (PD) is caused bymutations in the LRRK2 gene that encodes leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations, and particularly the most common mutation Gly2019Ser, are observed in patients withautosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD. The discoveries that pathogenic mutations inthe LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD. Recent investigations also suggest that LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies might, therefore, be beneficial in this common subtype of PD. In this Review, we describe the characteristics of LRRK2-associated PD that are most relevant to the development of LRRK2-targeted therapies and the design and implementation of clinical trials. We highlight strategies for correcting the effects of mutations inthe LRRK2 gene, focusing on how to identify which patients are the optimal candidates and how to decide on the timing of such trials. In addition, we discuss challenges in implementing trials of disease-modifying treatment in people who carry LRRK2 mutations.

Autophagy and LRRK2 in the Aging Brain.

Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the life-span of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson’s disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson’s disease is a hypokinetic, multisystemic disorder characterized by age-related, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson’s disease have been identified, among which mutations in the LRRK2 gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six LRRK2 mutations have been pathogenically linked to Parkinson’s disease, the most frequent being the G2019S in the kinase domain. LRRK2-associated Parkinson’s disease is clinically and neuropathologically similar to idiopathic Parkinson’s disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which LRRK2 mutations can lead to Parkinson’s disease. The present article will focus on the evidence that LRRK2 and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons in vitro and in LRRK2 knock-out, knock-in, kinase-dead and transgenic animals in vivo will be reviewed. The role of aging in LRRK2-induced synucleinopathy will be discussed. Possible mechanisms underlying the LRRK2-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of LRRK2 will be examined.

Gender differences in prevalence of LRRK2-associated Parkinson disease: A meta-analysis of observational studies

BackgroundThe gender effect in the prevalence of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson disease (PD) remains controversial. Herein, we conducted a meta-analysis to investigate the gender effect among these patients. MethodsPubMed and EMBASE databases were searched to identify the potential related studies published before December 2017. Case-control studies with separated data of sex and mutation status were included in further analyses. We pooled relative risk (RR) using fixed-effect model. The publication bias and sensitivity analyses were also performed. ResultsSixty-four studies with 32452 patients diagnosed with PD were included. Higher prevalence of female patients with LRRK2-associated PD was observed with a pooled RR of 1.22 (95% CI 1.14–1.30, P＜0.001). Further subgroup analyses showed that higher prevalence of female patients was only obtained in G2019S mutation patients (RR = 1.32, 95% CI 1.23–1.43, P＜0.001), but not in G2385R variant patients (RR = 1.03, 95% CI 0.91–1.17, P = 0.651). No significant heterogeneity and publication bias were observed in additional analyses. ConclusionsHigher female prevalence of LRRK2 mutation suggests roles of gender-related risk factors in PD patients, especially who carried G2019S mutation. Contrary to idiopathic PD, no sex difference was observed in prevalence of patients carried G2385R variant.

Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson's disease.

Cardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation. Short-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls. Beat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls. Increased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD.

Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids

SummaryRecent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

Investigating Voice as a Biomarker for Leucine-Rich Repeat Kinase 2-Associated Parkinson’s Disease

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts.

No evidence for DNM3 as genetic modifier of age at onset in idiopathic Parkinson's disease.

Parkinson's disease (PD) is a disorder with highly variable clinical phenotype. The identification of genetic variants modifying age at onset and other traits is of great interest because it may provide insight into disease mechanisms and potential therapeutic targets. A variant in the DNM3 gene (rs2421947) has been reported as a genetic modifier of age at onset in LRRK2-associated PD. To test the possible effect of genetic variation in DNM3 on age at onset in idiopathic PD, we examined rs2421947 in a total of 5918 patients with PD from seven data sets. We also assessed the potential effect of all common variants in the DNM3 locus. There was no significant association between rs2421947 and age at onset in any of the individual studies. Meta-analysis of the seven studies was nonsignificant and the between-study heterogeneity was minimal. No other common variants within the DNM3 locus affected age at onset. Inconclusion, we find no evidence of an association between DNM3 variants and age at onset in idiopathic PD.

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.

LRRK2-associated Parkinson's disease patients have better stereopsis than idiopathic Parkinson disease

ObjectivesVisual dysfunctions are frequent and have several manifestations in idiopathic Parkinson's disease (PD). However, the characteristics of these complications in LRRK2 (leucine-rich kinase 2)-associated PD patients still lack systematic research. The purpose of this study is to assess visual functions of LRRK2-associated PD patients. Patients and methodsTwenty-five (25) PD patients with LRRK2 R1628P and G2385R variants were included in the study and compared to 28 PD patients without these variants and 28 age-matched healthy controls. The genotypes of PD patients were kept double-blinded. Information on age, sex, disease duration, the movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS), Hoehn and Yahr staging scale (H&Y), Mini-Mental Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were included. Visual functions assessment included color perception, contrast sensitivity and stereopsis. ResultsPD patients with or without LRRK2 R1628P and G2385R variants have declined contrast sensitivity, diminished color discrimination and damaged stereopsis. There was no significant difference in retinal level visual deficiency (color discrimination and contrast sensitivity) between PD with LRRK2 variants and those without, but cortex level visual function, i.e. stereopsis is better in PD with LRRK2 variants than non-carrier PD patients. The associated factors of stereopsis are different. The stereopsis is associated with MoCA scores independently in non-carrier PD patients, but with UPDRSIII scores in LRRK2-associated PD patients. ConclusionsVisual functions are similarly affected in PD patients with and without LRRK2 R1628P and G2385R variants, but LRRK2-associated PD patients have better stereopsis than idiopathic PD patients.

Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers.

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain.