Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2

ObjectiveThe neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients.MethodsThirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia).ResultsThe mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PD-Dementia was diagnosed in 13.3% (n = 4) of R1441G-PD and 26.7% (n = 8) of i-PD patients (difference was not significant).ConclusionIn conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups.     

Molecular biology changes associated with LRRK2 mutations in Parkinson's disease

Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss in the substantia nigra. The recent discovery of leucine-rich-repeat kinase 2 gene (LRRK2) mutations in PD is significant because these mutations are the most common cause of autosomal dominant PD. Furthermore, a common recurrent mutation (G2019S) is associated with a significant proportion of nonfamilial PD, and a polymorphic variant (G2385R) has been found to increase the risk in the Asian race. The large LRRK2 protein of 280 kD contains three protein-protein interaction domains and two enzymatic domains, the Ras-related GTPase and the kinase. Mutations in these domains have been described in PD patients. Preliminary evidence suggests that some types of LRRK2 mutations increase the kinase activity, and this is associated with significantly higher apoptotic cell death in dopaminergic cell lines and primary neurons; abolishing the kinase function ameliorates this cellular toxicity. It also appears that its GTPase domain can be activated independently, whereas the kinase activity strictly requires the GTPase activation. Mutations in the LRRK2 have displayed notable pleomorphic pathologies that might indicate an upstream role of LRRK2 in cellular signaling pathways. The identification of physiological substrates (likely to be involved in signaling and apoptotic pathways) of LRRK2 remains an important step in our understanding of the role of LRRK2 in the disease process. Further in vitro and in vivo studies will unravel the role of LRRK2 in cell signaling and its impact on proliferation, differentiation, and survival of neurons.     

LRRK2 and Parkinson's disease in Norway

Objectives – Mutations in the LRRK2 gene have been associated with both familial and sporadic late-onset Parkinson's disease. A large number of mutations in this gene have been identified; however, for many of these variants, the pathogenicity and relative frequency are unknown. Herein, we investigate the frequency of a number of recently identified LRRK2 mutations in Norway. Methods – We genotyped eight putatively pathogenic LRRK2 mutations (R793M, R1067Q, I1371V, IVS31+3 A>G, M1869T, R1941H, T2356I and G2385R) in a series of 433 patients with Parkinson's disease and 587 controls from Norway. An intronic polymorphism previously reported to be associated with disease susceptibility was also examined (rs10506151). Results – The Lrrk2 R793M substitution was found in two healthy individuals. No other LRRK2 mutations were identified in the Norwegian population, and furthermore no association was observed between rs10506151 and Parkinson's disease ( P  = 0.41). Conclusions – LRRK2 mutations other than the Lrrk2 G2019S mutation are rare in Norway. Our results indicate that the Lrrk2 R793M substitution is most likely a rare polymorphism.     

Mouse models for LRRK2 Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes of both familial and sporadic PD. Animal models are critical tools in the attempt to understand the mechanisms of LRRK2-mediated pathogenesis. We have generated human Bacterial Artificial Chromosome (BAC) mediated transgenic mouse models expressing mutant LRRK2 that robustly recapitulate the behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent decrease in motor activity that is progressive and responds to treatment with levodopa. Pathologically, the most salient phenotype is early axonopathy of nigrostriatal dopaminergic neurons, accompanied by hyperphosphorylated tau. The mice also exhibit a consistent dopamine transmission deficit in both acute brain slices and live freely moving animals. Here we will discuss LRRK2 mouse models from several laboratories, their commonalities and differences, and offer scientific insights drawn from these studies.     

Common variants of LRRK2 are not associated with sporadic Parkinson's disease

Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.     

Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive and selective degeneration of nigrostriatal dopaminergic neurons. The discovery of at least six PD-causing genes in predominantly early-onset forms of the disorder has cemented a genetic component to the etiology. Notably, the discovery of mutations in the LRRK2 gene in patients presenting with typical 'sporadic' PD with ages at onset in their sixties and seventies has shifted paradigms in the field of PD research. The G2019S mutation in LRRK2 has been found in diverse populations worldwide and usually resides on a common haplotype revealing that many of these individuals share a common ancestor, probably of Middle Eastern origin. The only validated coding susceptibility alleles for PD, G2385R and R1628P, are both in this gene but to date have been found exclusively in Asian populations. Concomitant with genetic testing for PD is the need for appropriate and informed genetic counseling. Families of patients with LRRK2 mutations and susceptibility alleles need to be informed about the current lack of disease preventative strategies and the implications surrounding incomplete penetrance. In summary, single-handedly LRRK2 has had a major impact on the field of PD research and the findings have been of interest to both clinicians and scientists. We anticipate that other genes of such major impact exist for PD and look forward to their discovery.     

A novel P755L mutation in LRRK2 gene associated with Parkinson's disease

Parkinson's disease is a common neurodegenerative disorder. The identification of leucine-rich repeat kinase 2 (LRRK2) gene mutations as a cause of Parkinson's disease has greatly expanded our knowledge of the genetic and molecular pathogenesis of this disorder. By denaturing high-performance liquid chromatography and gene sequencing in patients and controls, we identified a novel frequent heterozygous 2264C-->T substitution, which causes a proline-to-leucine mutation (P755L) in LRRK2 gene. In our sample of 598 patients of Chinese Han ancestry, 12 cases carried the same LRRK2 mutation. Our results indicated that this single mutation was implicated in 2% of sporadic patients. We suggest that testing for this mutation will be important in the management and genetic counseling of patients with Parkinson's disease.     

LRRK2 variation and Parkinson's disease in African Americans

The global impact of LRRK2 mutations is yet to be realized with a lack of studies in specific ethnic groups, including those of Asian and African descent. Herein, we investigated the frequency of common LRRK2 variants by complete exon sequencing in a series of publicly available African American Parkinson's disease patients. Our study identified three novel synonymous exonic variants and 13 known coding variations; however, there did not appear to be any frequent (>5%) pathogenic mutations. Given the ethnic‐specific LRRK2 variation previously identified in PD further studies in under‐represented populations are warranted. © 2010 Movement Disorder Society.     

LRRK2 screening in a Canadian Parkinson's disease cohort

BACKGROUND: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have become the most common known cause for developing Parkinson's disease. The frequency of mutations described in the literature varies widely depending on the population studied with most reports focusing only on screening for the most common G2019S mutation in exon 41. METHODS: In this study seven exons (19, 24, 25, 31, 35, 38, and 41) in LRRK2 where mutations have been reported were screened in 230 unselected Parkinson's disease patients using denaturing high-performance liquid chromatography. RESULTS: The sequencing of samples with heteroduplex profiles revealed five novel and two known intronic sequence variants. In our cohort, we were unable to detect any of the known mutations in these exons or identify novel mutations within the LRRK2 gene. CONCLUSIONS: Therefore, despite the availability of diagnostic LRRK2 genetic testing it is unlikely to yield a positive result in this population.     

Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Val mutation.

Leucine-Rich Repeat Kinase 2 (LRRK2) gene mutations are the most common known cause of Parkinson's disease (PD), but neuropathological studies are available on very few patients with LRRK2 mutation. The reported findings range from Lewy body-positive pathology to different pathologies, including nigral degeneration without distinctive features, neuronal loss with only ubiquitin-positive inclusions, and tau-positive-only pathology. Here we report the first neuropathological study in an Italian PD case carrying a different LRRK2 mutation, Ile1371Val, and showing typical ubiquitin- and alpha-synuclein-positive Lewy body pathology. These findings support the concept that the neurodegeneration associated with LRRK2 mutations might be clinically and pathologically indistinguishable from typical PD.     

A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson's disease

The Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a disease susceptibility gene for Parkinson's disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950-3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation.     

LRRK2 mutations in a clinic-based cohort of Parkinson's disease

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2 , encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n  = 202, controls: n  = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.     

Cognitive impairments associated with early Parkinson's disease

We administered a battery of cognitive tests to 41 recently diagnosed Parkinson patients and 41 controls to assess the early neuropsychological changes associated with Parkinson's disease (PD). Parkinson subjects did as well as controls on tasks assessing attention and select language and visuospatial measures. However, PD subjects did significantly worse on embedded figures, facial recognition, proverbs, and verbal and figural memory measures, and made more perseverative responses on a set shifting task. A discriminant function of measures of proverbs, embedded figures, and memory accounted for 22% of the variance between groups. These data suggest that the cognitive changes in early PD are more pervasive than originally described and may reflect the onset of a more widespread pathologic process.