Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510G→A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019Ser), in idiopathic Parkinson's disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1·6%) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinson's disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease.
"mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal dominant PD and cause 2– 5% of familial PD. The most common point mutation, G2019S, has been shown to be involved in 5–6% of autosomal dominant PD cases (Di Fonzo et al., 2005; Nichols et al., 2005; Dächsel and Farrer, 2010) and 1–2% of sPD cases (Gilks et al., 2005). Patients with late-onset monogenic forms of PD may demonstrate subtle signs or symptoms several years before they suffer from any motor symptoms (Sossi et al., 2010; Johansen et al., 2011; Ruiz- Martínez et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene are the most common cause of autosomal dominant Parkinson's disease (PD). To assess the cerebrospinal fluid (CSF) levels of α-synuclein oligomers in symptomatic and asymptomatic leucine-rich repeat kinase 2 mutation carriers, we used enzyme-linked immunosorbent assays (ELISA) to investigate total and oligomeric forms of α-synuclein in CSF samples. The CSF samples were collected from 33 Norwegian individuals with leucine-rich repeat kinase 2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic leucine-rich repeat kinase 2 mutation carriers. We also included 35 patients with sporadic PD (sPD) and 42 age-matched healthy controls. Levels of CSF α-synuclein oligomers were significantly elevated in healthy asymptomatic individuals carrying leucine-rich repeat kinase 2 mutations (n = 20; P < 0.0079) and in sPD group (n = 35; P < 0.003) relative to healthy controls. Increased α-synuclein oligomers in asymptomatic leucine-rich repeat kinase 2 mutation carriers showed a sensitivity of 63.0% and a specificity of 74.0%, with an area under the curve of 0.66, and a sensitivity of 65.0% and a specificity of 83.0%, with an area under the curve of 0.74 for sPD cases. An inverse correlation between CSF levels of α- synuclein oligomers and disease severity and duration was observed. Our study suggests that quantification of α-synuclein oligomers in CSF has potential value as a tool for PD diagnosis and presymptomatic screening of high-risk individuals.
"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
"We identified additional FTSEC biomarkers that represent novel candidate HGSOC biomarkers. These include LRRK2, a gene that encodes a kinase involved in Parkinsons Disease [29,30]. LRRK2 has not previously been implicated in ovarian cancer development but analyses of The Cancer Genome Atlas (TCGA) data suggests ~3% of primary HGSOCs harbor somatic mutations in this gene [31-33]. "
[Show abstract][Hide abstract] ABSTRACT: Fallopian tube secretory epithelial cells (FTSECs) have been implicated as a cell-of-origin for high-grade serous epithelial ovarian cancer. However, there are relatively few in vitro models of this tissue type available for use in studies of FTSEC biology and malignant transformation. In vitro three-dimensional (3D) cell culture models aim to recreate the architecture and geometry of tissues in vivo and restore the complex network of cell-cell/cell-matrix interactions that occur throughout the surface of the cell membrane.
We have established and characterized 3D spheroid culture models of primary FTSECs. FTSEC spheroids contain central cores of hyaline matrix surrounded by mono- or multi-layer epithelial sheets. We found that 3D culturing alters the molecular characteristics of FTSECs compared to 2D cultures of the same cells. Gene expression profiling identified more than a thousand differentially expressed genes between 3D and 2D cultures of the same FTSEC lines. Pathways significantly under-represented in 3D FTSEC cultures were associated with cell cycle progression and DNA replication. This was also reflected in the reduced proliferative indices observed in 3D spheroids stained for the proliferation marker MIB1. Comparisons with gene expression profiles of fresh fallopian tube tissues revealed that 2D FTSEC cultures clustered with follicular phase tubal epithelium, whereas 3D FTSEC cultures clustered with luteal phase samples.
This 3D model of fallopian tube secretory epithelial cells will advance our ability to study the underlying biology and etiology of fallopian tube tissues and the pathogenesis of high-grade serous epithelial ovarian cancer.
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