Highlights • The PD-linked LRRK2(R1441G) mutation destabilizes F-actin in synaptic terminals. • LRRK2(G2019S) increases susceptibility of F-actin to Latrunculin in human fibroblasts. • LRRK2(G2019S) ...increases F-actin bundling and decreases filopodial length in human fibroblasts. • Lack of LRRK2 age-dependently alters GluN2A integration into the postsynaptic density. • Lack of LRRK2 decreases phosphatidylserine externalization at synaptic terminals.
Background and purpose
The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2) is highly variable, suggesting a strong influence of modifying factors. In this ...context, inflammation is a potential candidate inducing clinical subtypes.
Methods
An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor.
Results
Patients classified as diffuse/malignant presented with the highest levels of the pro‐inflammatory proteins interleukin 8 (IL‐8), monocyte chemotactic protein 1 (MCP‐1) and macrophage inflammatory protein 1‐β (MIP‐1‐β) paralleled by high levels of the neurotrophic protein brain‐derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis.
Conclusions
Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non‐motor symptoms. The pro‐inflammatory metabolites IL‐8, MCP‐1 and MIP‐1‐β as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.
Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We ...aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.
Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers.
All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.
Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.
The LRRK2(G2019S) mutation is the most common identifiable cause for Parkinson disease (PD), but the underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired ...mitochondrial function and morphology have been described in different in vivo and in vitro model systems of early-onset PD (EOPD) as well as in EOPD patient tissue. The aim of our study was to assess mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue to determine whether impaired mitochondrial function and morphology are shared features in early-onset and late-onset PD.
Skin biopsies were taken from 5 patients with PD with the LRRK2(G2019S) mutation. Assessment of mitochondrial membrane potential and intracellular ATP levels as well as substrate-linked mitochondrial ATP production assays were all carried out on 3 independent cell preparations per patient. Results were compared to 5 age-matched controls. Mitochondrial elongation and interconnectivity was assessed using previously published methods.
Both mitochondrial membrane potential and total intracellular ATP levels were decreased in the G2019S mutation carriers. Subsequently undertaken mitochondrial ATP production assays suggested that the observed reduction is at least partially due to impaired mitochondrial function. Mitochondrial elongation and interconnectivity were increased in the LRRK2(G2019S) patient cohort.
Our results provide evidence for impaired mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue. Further studies are required to determine whether the impaired mitochondrial function is due to increased LRRK2 kinase activity or other mechanisms such as LRRK2 haploinsufficiency.
The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau ...species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.
CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.
Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.
The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.
Objective
The aim of the study was to examine the sense of smell in LRRK2 mutation carriers and in patients with sporadic PD (sPD).
Materials and Methods
A total of 343 individuals were included: 275 ...sPD of whom 90 were de novo patients with sPD, 17 LRRK2 PD, 36 healthy LRRK2 mutation carriers, and 15 healthy family members without mutation. All subjects underwent neurologic examination and olfactory sense testing with B‐SIT (a 12–item test). Linear regression analysis was applied to build different models with B‐SIT as dependent variable.
Results
Sporadic PD had significantly lower scores in olfaction compared with LRRK2 PD (P < 0.001). B‐SIT scores were lowest in medicated sPD, and higher scores were found in de novo patients. LRRK2 PD had similar sense of smell to healthy LRRK2 mutation carriers and to healthy family members without mutation when adjusting for age.
Conclusion
Hyposmia was pronounced already at time of diagnosis in the sPD cases but was not present in healthy LRRK2 mutation carriers and less pronounced in LRRK2 PD compared with sporadic cases. Smell testing may be a preclinical marker in sporadic PD but does not seem applicable in LRRK2 cases.
Several pathogenic mutations in the leucine‐rich repeat kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism. We screened 435 Norwegian patients diagnosed ...with Parkinson's disease and 519 control subjects for the presence of 7 LRRK2 mutations. Nine patients from seven families were found to be heterozygote carriers of the LRRK2 6055G>A (G2019S) mutation. Twelve of 28 first‐degree relatives also carried the mutation, but only 1 had Parkinson's disease. The clinical features included asymmetric resting tremor, bradykinesia, and rigidity with a good response to levodopa and could not be distinguished from idiopathic Parkinson's disease. Ann Neurol 2005;57:762–765
An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson disease (PD) was recently reported in Ashkenazi Jews. The authors screened a series of 311 Norwegian patients with ...PD and 474 controls for 2 common functional mutations of the GBA protein, N370S and L444P. Seven patients (2.3%) and 8 controls (1.7%) carried a mutant GBA allele (p = 0.58). This study does not indicate increased susceptibility to PD in GBA mutations carriers in Norway.
Objectives – Previous studies have found associations between Parkinson’s disease (PD) and polymorphisms located within both the alpha‐synuclein gene (SNCA) promoter and other gene regions. Our aim ...was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease.
Methods – We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3′ gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed.
Results – Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263‐bp allele, rs356165 and rs356219).
Conclusion – LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3′ regions.
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