Leucine-rich Repeat Kinase 2 Mutation Carriers Research Articles

High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry.

The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients.

Low-variance RNAs identify Parkinson's disease molecular signature in blood.

The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.

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.

Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers

Converging evidence suggests that the Parkinson’s disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cellular function by regulating actin dynamics. In the present study we investigate the role of LRRK2 in functional synaptic terminals of adult LRRK2-knockout and LRRK2(R1441G)-transgenic mice as well as in primary fibroblasts of LRRK2(G2019S) mutation carriers. We show that lack of LRRK2 decreases and overexpression of mutant LRRK2 age-dependently increases the effect of the actin depolymerizing agent Latrunculin A (LatA) on the synaptic cytoskeleton. Similarly, endogenous mutant LRRK2 increases sensitivity to LatA in primary fibroblasts. Under basal conditions however, these fibroblasts show an increase in F-actin bundles and a decrease in filopodial length which can be rescued by LatA treatment. Our data suggest that LRRK2 alters actin dynamics and F-actin structure both in brain neurons and skin fibroblasts. We hypothesize that increased F-actin bundling represents a compensatory mechanism to protect F-actin from the depolymerizing effect of mutant LRRK2 under basal conditions. Our data further indicate that LRRK2-dependent changes in the cytoskeleton might have functional consequences on postsynaptic NMDA receptor localization.

A voxel‐based morphometry and diffusion tensor imaging analysis of asymptomatic Parkinson's disease‐related G2019S LRRK2 mutation carriers

Patients with Parkinson's disease have reduced gray matter volume and fractional anisotropy in both cortical and sub-cortical structures, yet changes in the pre-motor phase of the disease are unknown. A comprehensive imaging study using voxel-based morphometry and diffusion tensor imaging tract-based spatial statistics analysis was performed on 64 Ashkenazi Jewish asymptomatic first degree relatives of patients with Parkinson's disease (30 mutation carriers), who carry the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene. No between-group differences in gray matter volume could be noted in either whole-brain or volume-of-interest analysis. Diffusion tensor imaging analysis did not identify group differences in white matter areas, and volume-of-interest analysis identified no differences in diffusivity parameters in Parkinson's disease-related structures. G2019S carriers do not manifest changes in gray matter volume or diffusivity parameters in Parkinson's disease-related structures prior to the appearance of motor symptoms.

Genetic Screening for the LRRK2 R1441C and G2019S Mutations in Parkinsonian Patients from Campania

PARK8 is the most common known mendelian form of Parkinson's Disease (PD). It is due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene and G2019S is considered the most frequent mutation in the Caucasian population, in particular in the Southern Europe and Mediterranean countries. We assessed the frequency of the G2019S and R1441C/H/G mutations in 513 (311 M and 202 F) unrelated PD patients from Campania, in Southern Italy. Three hundreds and thirty-six patients presented a sporadic disease, and 177 had a familial history of PD or tremor. Three hundreds and eighty cases originated from the province of Naples. We compared our LRRK2 mutation carriers to idiopathic PD patients matched for recruiting center, gender, age and age at onset. Thirteen patients (8 M and 5 F) carried the R1441C mutation and 4 (3 M and 1 F) the G2019S mutation, all in heterozygous state. All carriers originated from the province of Naples. No carriers of the R1441H or R1441G mutations were found. The LRRK2 mutation carriers were clinically similar to idiopathic PD patients. The R1441C and G2019S mutations are not rare causes of PD in Campania, especially in the province of Naples and among the familial cases, where the overall mutation prevalence is 6.8%. The R1441C prevalence was higher than that of G2019S (2.5% vs 0.8%), underlining the importance of the geographical differencies in LRRK2 mutation frequency for molecular screening and genetic counseling of PD patients.

Behavioral deficits and striatal DA signaling in LRRK2 p.G2019S transgenic rats: a multimodal investigation including PET neuroimaging.

A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2 p.G2019S rats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. Neuroimaging using dopaminergic PET did not recapitulate prior studies in human LRRK2 mutation carriers. Consistently, LRRK2 p.G2019S rats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities.

Neural correlates of executive functions in healthy G2019S LRRK2 mutation carriers

IntroductionThe G2019S mutation in the leucine rich repeat kinase 2 (LRRK2) gene is prevalent among Ashkenazi Jewish patients with Parkinson's disease (PD). Cognitive deficits are common in early stage PD. We aimed to characterize the effect of the G2019S mutation on neural mechanisms of executive function processing by testing whether healthy mutation carriers who are an “at risk” population for the future development of PD differed from non-carriers on an functional magnetic resonance imaging (fMRI) Stroop interference task. MethodsCognitive performance and task related cerebral activity were measured in 40 healthy first-degree relatives of Ashkenazi PD patients (19 carriers and 21 non-carriers of the G2019S mutation). Both regional differences in neural activity and seed region driven functional connectivity methods were performed using fMRI. ResultsCompared to non-carriers, mutation carriers had greater baseline deactivation and increased task related activity in the right inferior parietal lobe, right precuneus and right fusiform gyrus. Whole brain functional connectivity analysis revealed stronger coupling between these regions and both basal ganglia structures as well as cortical regions in the carrier group. Non-manifesting G2019S mutation carriers and non-carriers performed similarly on the task and on all other assessed measures, so behavioral differences in task performance and baseline cognitive functions cannot explain the observed imaging differences. ConclusionsG2019S carriers, at risk for developing PD, had similar behavioral performance as non-carriers during the Stroop task, but increased activity in brain regions that have previously been found to be part of the ventral attention system together with stronger coupling between task related areas and structures that make up the ventral and dorsal attention system as well as the basal ganglia-thalamocortical network. This suggests a neural compensatory mechanism that enables intact cognitive performance in asymptomatic mutation carriers.

DJ-1 and αSYN in LRRK2 CSF do not correlate with striatal dopaminergic function

Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson's disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and methylphenidate binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.

Clinical and brain imaging characteristics in leucine‐rich repeat kinase 2–associated PD and asymptomatic mutation carriers

The objective of this research was to evaluate a possible endophenotype in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Ten symptomatic LRRK2 patients, 24 sporadic Parkinson's disease patients as well as 10 asymptomatic LRRK2 mutation carriers and 29 matched healthy controls underwent comprehensive clinical assessments with respect to motor and non-motor symptoms. Transcranial sonography and magnetic resonance imaging (voxel-based morphometry [VBM]) were assessed to evaluate morphological imaging characteristics. LRRK2 patients had an earlier onset of motor symptoms and a more benign phenotype of motor and non-motor characteristics compared to sporadic Parkinson's disease patients. However, depression scores were higher in LRRK2 patients. No clinical differences were found regarding motor and non-motor symptoms in asymptomatic LRRK2 mutation carriers in comparison to controls. Transcranial sonography showed hyperechogenicity of the substantia nigra in both patients' cohorts as well as in asymptomatic LRRK2 mutation carriers. Voxel-based morphometry revealed increased gray matter volume of the cerebellum and precentral gyrus in LRRK2 patients and of the cuneus in asymptomatic LRRK2 mutation carriers. In contrast, we found decreased basal ganglia gray matter volume in LRRK2 patients compared to controls. Increased gray matter volume of different anatomical structures associated with motor loops in LRRK2 patients and asymptomatic LRRK2 mutation carriers compared to age-matched sporadic Parkinson's disease patients and controls might indicate compensatory mechanism in LRRK2 mutation carriers due to motor network plasticity not only in the symptomatic stage of the disease but even in the premotor phase. Substantia nigra hyperechogenicity in yet unaffected LRRK2 mutation carriers indicates morphologic alterations in an asymptomatic stage of disease.

Leucine-Rich Repeat Kinase 2 Is Associated With the Endoplasmic Reticulum in Dopaminergic Neurons and Accumulates in the Core of Lewy Bodies in Parkinson Disease

Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequent genetic cause of Parkinson disease (PD). To understand the role of LRRK2 in the neuropathology of PD, we investigated the protein expression in a healthy brain and brains from patients with PD and its subcellular localization in dopaminergic neurons. LRRK2 was found to be widely expressed in healthy adult brain, including areas involved in PD. By double fluorescent staining, we found that endogenous LRRK2 is colocalized with the endoplasmic reticulum (ER) markers Neurotrace and KDEL in human dopaminergic neurons. Labeling of brain sections with anti-LRRK2 and anti-α-synuclein antibodies revealed localization of LRRK2 in the core of 24% of Lewy bodies (LBs) in the substantia nigra and 11% of LBs in the locus coeruleus in idiopathic PD patients. The percentage was increased to 50% in both areas in a patient with the G2019S LRRK2 mutation. The finding of ER localization suggests the possibility that LRRK2 is involved in the ER stress response and could account for the susceptibility to neuronal degeneration of LRRK2 mutation carriers. The localization of LRRK2 protein in the core of a subset of LBs demonstrates the contribution of LRRK2 to LB formation and disease pathogenesis.

LRRK2 in Parkinson’s disease: genetic and clinical studies from patients

Mutations in leucine-rich repeat kinase 2 (LRRK2) (PARK8) are associated with both familial and sporadic forms of Parkinson's disease. Most studies have shown that LRRK2 mutations may explain between 5% and 13% of familial and 1-5% of sporadic Parkinson's disease. Importantly, a common recurrent mutation (G2019S) located in the kinase domain has been reported across most ethnic populations, with the highest prevalence among Ashkenazi Jews and North African Arabs. A recent worldwide meta-analysis pooling data from 24 populations reported a higher occurrence of G2019S in southern than in northern European countries and the penetrance is estimated to be approximately 75% at the age of 79 years. The R1441 'hotspot' amino acid codon residue (G/H/C) in the Ras of complex proteins domain is the second most common site of pathogenic LRRK2 substitutions after G2019S, with most carriers developing symptoms by the age of 75 years. Two polymorphic variants found almost exclusively among Asians (G2385R and R1628P) have been shown to increase the Parkinson's disease risk by approximately two-fold. The mutational event associated with R1628P is more recent, occurring approximately 2500 years ago, compared to estimates of 4000 years for G2385R carriers. LRRK2 mutation carriers generally simulate late onset Parkinson's disease and present with the usual typical clinical features. Genetic testing for G2019S in sporadic late-onset Parkinson's disease can be considered in some situations and may be useful in populations with high carrier status. The identification of asymptomatic mutation and risk variant carriers provides a unique opportunity for recruiting these subjects in potential neuroprotective trials and longitudinal studies to identify biomarkers of neurodegeneration.

A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease

Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of...

LRRK2p.G2019S Mutation Is Not Common among Alzheimer’s Disease Patients in Brazil

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson’s Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer’s Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.

LRRK2 p.G2019S mutation is not common among Alzheimer's disease patients in Brazil.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson’s Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer’s Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.

Genetic factors influencing age at onset in LRRK2-linked Parkinson disease

Patients with Leucine-rich repeat kinase 2 ( LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein ( SNCA) and tau ( MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.

The Gly2019Ser mutation in LRRK2is not fully penetrant in familial Parkinson's disease: the GenePD study

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

LRRK2 is a component of granular alpha‐synuclein pathology in the brainstem of Parkinson's disease

Classical Parkinson's disease (PD) is characterized by the appearance of Lewy bodies (LBs) in affected brain regions, showing mostly compact alpha-synuclein deposition, in contrast with punctate or granular deposition, hypothesized to represent early stages of aggregation. Leucine-rich repeat kinase 2 (LRRK2) is the commonest mutated gene in inherited and idiopathic PD. LRRK2 mutation carriers display a diverse neuropathology, including alpha-synuclein and tau inclusions, suggesting an upstream role for LRRK2 in protein aggregation. We studied LRRK2 expression throughout the normal human brain with three different antibodies. We also examined the pattern of LRRK2 expression in relation to alpha-synuclein aggregation and LB formation in the brainstem of sporadic LB disease. Physiological LRRK2 expression was not restricted to regions preferentially affected in PD and LRRK2 often localized to the nuclear envelope in addition to the known cytoplasmic expression. In PD, we were able to consistently detect LRRK2 in the halo of a minority (approximately 10%) of nigral LBs using three different antibodies. Only one antibody detected LRRK2 in the core of approximately 80% of classic LBs. In the lower brainstem, most notably in the dorsal motor nucleus of the vagus, we found previously unrecognized LRRK2 labelling of complex globular lesions, filled with LB-like matter showing a punctate or granular staining for alpha-synuclein. This was often accompanied by strong LRRK2 expression within dystrophic neurites. Our findings confirm widespread physiological LRRK2 expression in the human brain and suggest an association of LRRK2 with possible early-stage alpha-synuclein pathology in the brainstem of PD.

P.5.d.001 Expression of alpha-synuclein in patients with Parkinson's disease caused by mutations in the LRRK2 gene

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were initially identified in large families with autosomal dominant Parkinson disease (PD). These mutations (p.R1441C, p.R1441G, p.Y1699C and p.I2020T) revealed that genetic mutations could cause clinically typical, late-onset PD. Subsequently, the p.G2019S mutation was found to be a frequent cause of both autosomal dominant and “sporadic” PD, particularly in populations in North Africa or the Middle East. Two Lrrk2 protein substitutions (p.R1628P and p.G2385R) have since been associated with susceptibility to PD in Asian populations. More than a hundred variants have been identified in the LRRK2 gene, but pathogenicity is most convincing for the p.R1441H substitution. The role in PD remains unknown for other variants because segregation with disease has not been shown. Screening these variants in very large patient-control series may help clarify their role in PD. Lrrk2 is a large, multidomain protein with pathogenic mutations occurring in several functional domains. Cell biological experiments have shown that the p.G2019S mutation increase kinase activity. This is consistent with the observation that homozygous p.G2019S carriers do not have earlier disease onset or more severe disease compared with heterozygous carries. It is now necessary to identify the regulators and substrates of Lrrk2 in order to understand the effect of each LRRK2 mutation. The identification of a large number of presymptomatic LRRK2 mutation carriers provides a unique possibility for future studies on neuroprotection. However, more insight into the basic function of Lrrk2 is needed in order to exploit this potential for translational research.