We detected a missense mutation in the kinase domain of the LRRK2 gene in members with autosomal dominant Parkinson's disease of the Japanese family (the Sagamihara family) who served as the basis for the original defining of the PARK8 Parkinson's disease locus. The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure-pathogenesis relationship for the gene product of LRRK2. We did not detect this mutation or other known mutations of the LRRK2 gene in Japanese patients with sporadic Parkinson's disease.
"In contrast to the activating effect of the G2019S variation on LRRK2 kinase domain, the PD-associated I2020T variation induces a modest increase or has no effect on the ability of LRRK2 kinase domain to phosphorylate exogenous protein/peptide substrates [Funayama et al., 2005; Ohta et al., 2007; Nichols et al., 2010]. Furthermore, I2020T variation significantly reduces phosphorylation of recombinant LRRK2 at Ser-910 and Ser-935 in transfected HEK293 cells [Nichols et al., 2010]. "
[Show abstract][Hide abstract] ABSTRACT: Genetic variations of leucine-rich repeat kinase 2 (LRRK2) are the major cause of dominantly inherited Parkinson disease (PD). LRRK2 protein contains seven predicted domains: a tandem Ras-like GTPase (ROC) domain and C-terminal of Roc (COR) domain, a protein kinase domain and four repeat domains. PD-causative variations arise in all domains, suggesting that aberrant functioning of any domain can contribute to neurotoxic mechanisms of LRRK2. Determination of the three-dimensional structure of LRRK2 is one of the best avenues to decipher its neurotoxic mechanism. However, with the exception of the Roc domain, the three-dimensional structures of the functional domains of LRRK2 have yet to be determined. Based upon the known three-dimensional structures of repeat domains of other proteins, the tandem Roc-COR domains of the C. tepidum Rab family protein, and the kinase domain of the D. discoideum Roco4 protein, we predicted (i) the motifs essential for protein-protein interactions in all domains, (ii) the motifs critical for catalysis and substrate recognition in the tandem Roc-COR and kinase domains, and (iii) the effects of some PD-associated missense variations on the neurotoxic action of LRRK2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK2. This article is protected by copyright. All rights reserved.
Human Mutation 04/2014; 35(4). DOI:10.1002/humu.22515 · 5.14 Impact Factor
"Several mutations in LRRK2 clearly segregate with the disease, and, importantly, these mutations cluster within the two catalytic domains, suggesting that a change in enzymatic functions (GTPase and/or kinase) may mediate the pathogenic effects of LRRK2 . R1441G/C/H mutations map to the ROC domain [4,7,8], Y1669C to the COR domain , and I2020T and G2019S mutations to the kinase domain [9,10]. In this frame, the G2019S mutation is by far the most common pathogenic LRRK2 mutation, and is responsible for more than 10% of familial PD cases and 1 to 2% of sporadic PD cases . "
[Show abstract][Hide abstract] ABSTRACT: It is now well established that chronic inflammation is a prominent feature of several neurodegenerative disorders including Parkinson's disease (PD). Growing evidence indicates that neuroinflammation can contribute greatly to dopaminergic neuron degeneration and progression of the disease. Recent literature highlights that leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in both autosomal-dominantly inherited and sporadic PD cases, modulates inflammation in response to different pathological stimuli. In this review, we outline the state of the art of LRRK2 functions in microglia cells and in neuroinflammation. Furthermore, we discuss the potential role of LRRK2 in cytoskeleton remodeling and vesicle trafficking in microglia cells under physiological and pathological conditions. We also hypothesize that LRRK2 mutations might sensitize microglia cells toward a pro-inflammatory state, which in turn results in exacerbated inflammation with consequent neurodegeneration.
Journal of Neuroinflammation 03/2014; 11(1):52. DOI:10.1186/1742-2094-11-52 · 5.41 Impact Factor
"At the histopathological level, PD is characterized by dopaminergic neuronal loss in the substantia nigra and striatum, combined with the formation of intracellular Lewy bodies in degenerating neurons . Mutations in LRRK2 represent a large genetic component of both familial and sporadic PD , . The LRRK2 gene encodes a large (∼280 kDa) multidomain protein harbouring both GTPase and kinase activities (reviewed in ). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of genetic Parkinson's disease (PD). The biological function of LRRK2 and how mutations lead to disease remain poorly defined. It has been proposed that LRRK2 could function in gene transcription regulation; however, this issue remains controversial. Here, we investigated in parallel gene and microRNA (miRNA) transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout (KO) mice, as well as mice expressing human LRRK2 wildtype (hLRRK2-WT) or the PD-associated R1441G mutation (hLRRK2-R1441G). We identified a total of 761 genes and 24 miRNAs that were misregulated in the absence of LRRK2 when a false discovery rate of 0.2 was applied. Notably, most changes in gene expression were modest (i.e., <2 fold). By real-time quantitative RT-PCR, we confirmed the variations of selected genes (e.g., adra2, syt2, opalin) and miRNAs (e.g., miR-16, miR-25). Surprisingly, little or no changes in gene expression were observed in mice expressing hLRRK2-WT or hLRRK2-R1441G when compared to non-transgenic controls. Nevertheless, a number of miRNAs were misexpressed in these models. Bioinformatics analysis identified several miRNA-dependent and independent networks dysregulated in LRRK2-deficient mice, including PD-related pathways. These results suggest that brain LRRK2 plays an overall modest role in gene transcription regulation in mammals; however, these effects seem context and RNA type-dependent. Our data thus set the stage for future investigations regarding LRRK2 function in PD development.
PLoS ONE 01/2014; 9(1):e85510. DOI:10.1371/journal.pone.0085510 · 3.23 Impact Factor
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