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Lrrk2 mutations in South America: A study of Chilean Parkinson's disease.

ABSTRACT: Pathogenic substitutions in the leucine-rich repeat kinase 2 protein (Lrrk2), R1441G and G2019S, are a prevalent cause of autosomal dominant and sporadic Parkinson's disease in the Northern Spanish population. In this study we examined the frequency of these two substitutions in 166 Parkinson's disease patients and 153 controls from Chile, a population with Spanish/European-Amerindian admixture. Lrrk2 R1441G was not observed, however Lrrk2 G2019S was detected in one familial and four sporadic Parkinson's disease patients. These findings suggest Lrrk2 G2019S may play an important role in Parkinson's disease on the South American Continent and further studies are now warranted.

SUBMITTER: Perez-Pastene C

PROVIDER: S-EPMC1986707 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Lrrk2 mutations in South America: A study of Chilean Parkinson's disease.

Perez-Pastene Carolina C Cobb Stephanie A SA Díaz-Grez Fernando F Hulihan Mary M MM Miranda Marcelo M Venegas Pablo P Godoy Osvaldo Trujillo OT Kachergus Jennifer M JM Ross Owen A OA Layson Luis L Farrer Matthew J MJ Segura-Aguilar Juan J

Neuroscience letters 20070617 3

Pathogenic substitutions in the leucine-rich repeat kinase 2 protein (Lrrk2), R1441G and G2019S, are a prevalent cause of autosomal dominant and sporadic Parkinson's disease in the Northern Spanish population. In this study we examined the frequency of these two substitutions in 166 Parkinson's disease patients and 153 controls from Chile, a population with Spanish/European-Amerindian admixture. Lrrk2 R1441G was not observed, however Lrrk2 G2019S was detected in one familial and four sporadic Pa ...[more]

PMID: 17614198

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Lrrk2 p.Q1111H substitution and Parkinson's disease in Latin America.

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Project description:This SuperSeries is composed of the SubSeries listed below.

2015-12-01 | GSE51923 | GEO

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Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.

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Idiopathic and LRRK2-associated Parkinson's disease

Project description:Idiopathic and LRRK2-associated Parkinson's disease

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LRRK2 activation in idiopathic Parkinson's disease.

Project description:Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphorylation of LRRK2 and, separately, the dissociation of 14-3-3 proteins from LRRK2. Using these proximity ligation assays, we show that wild-type LRRK2 kinase activity was selectively enhanced in substantia nigra dopamine neurons in postmortem brain tissue from patients with iPD and in two different rat models of the disease. We show that this occurred through an oxidative mechanism, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities in mitochondrial protein import and lysosomal function. Our study suggests that, independent of mutations, wild-type LRRK2 plays a role in iPD. LRRK2 kinase inhibitors may therefore be useful for treating patients with iPD who do not carry LRRK2 mutations.

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Models of LRRK2-Associated Parkinson's Disease.

Project description:Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic causes of Parkinson's disease (PD) and also one of the strongest genetic risk factors in sporadic PD. The LRRK2 protein contains a GTPase and a kinase domain and several protein-protein interaction domains. Both in vitro and in vivo assays in different model systems have provided tremendous insights into the molecular mechanisms underlying LRRK2-induced dopaminergic neurodegeneration. Among all the model systems, animal models are crucial tools to study the pathogenesis of human disease. How do the animal models recapitulate LRRK2-induced dopaminergic neuronal loss in human PD? To answer this question, this review focuses on the discussion of the animal models of LRRK2-associated PD including genetic- and viral-based models.

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LRRK2 mutations in Parkinson's disease: confirmation of a gender effect in the Italian population.

Project description:BackgroundThe relative risk of developing idiopathic PD is 1.5 times greater in men than in women, but an increased female prevalence in LRRK2-carriers has been described in the Ashkenazi Jewish population. We report an update about the frequency of major LRRK2 mutations in a large series of consecutive patients with Parkinson's disease (PD), including extensive characterization of clinical features. In particular, we investigated gender-related differences in motor and non-motor symptoms in the LRRK2 population.Methods2976 unrelated consecutive Italian patients with degenerative Parkinsonism were screened for mutations on exon 41 (G2019S, I2020T) and a subgroup of 1190 patients for mutations on exon 31 (R1441C/G/H). Demographic and clinical features were compared between LRRK2-carriers and non-carriers, and between male and female LRRK2 mutation carriers.ResultsLRRK2 mutations were identified in 40 of 2523 PD patients (1.6%) and not in other primary parkinsonian syndromes. No major clinical differences were found between LRRK2-carriers and non-carriers. We found a novel I2020L missense variant, predicted to be pathogenic. Female gender was more common amongst carriers than non-carriers (57% vs. 40%; p = 0.01), without any gender-related difference in clinical features. Family history of PD was more common in women in the whole PD group, regardless of their LRRK2 status.ConclusionsPD patients with LRRK2 mutations are more likely to be women, suggesting a stronger genetic load compared to idiopathic PD. Further studies are needed to elucidate whether there is a different effect of gender on the balance between genetic and environmental factors in the pathogenesis of PD.

| S-EPMC4144811 | biostudies-literature

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