The Role of TMEM230 Gene in Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Deng H
PROVIDER: S-EPMC6218139 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:A study on familial Parkinson disease (PD) described 4 variants in the gene TMEM230 (Chr. 20p13) as the cause of PD. The aim of this study was to test if variants in the TMEM230 gene are associated with PD in 2 independent American European data sets. No variants in the TMEM230 region were found associated with PD, age at onset, or cerebrospinal fluid ?-synuclein levels.
| S-EPMC5526081 | biostudies-literature
Project description:Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.
| S-EPMC6047531 | biostudies-literature
Project description:TMEM230 mutations have been recently reported to cause autosomal dominant Parkinson's disease (PD). However, there are limited studies from different ethnic populations to support the role of TMEM230 in sporadic PD. In this study, we performed a comprehensive TMEM230 mutation screening in 550 sporadic PD patients and 560 controls to elaborate the genetic contribution of TMEM230 to sporadic PD. Overall, we did not find any pathogenic mutations in the coding sequence, while we identified four variants (c.68 + 182G > A, c.78A > G, c.552 + 11A > G and c.174 + 11C > T) both in the patients and controls, and c.68 + 182G > A appeared to be associated with an increased risk of PD (odds ratio 1.782, 95% confidence interval 1.035-3.067, p < 0.05). After Bonferroni correction, however, c. 68 + 182G > A had no significant association with sporadic PD (p c = 0.136, p c > 0.05). Thus our results suggest that TMEM230 gene mutations may be rare in Chinese populations, and the variability of TMEM230 gene may not be a main factor for sporadic PD patients in Chinese Han populations. More evidence is still needed to clarify this question.
| S-EPMC5430725 | biostudies-literature
Project description:TMEM230 has been associated with autosomal dominant Parkinson's disease (PD). Subsequent studies have remained negative, and none of previous described mutation has been reported anymore. We investigated the implication of this gene in the PD in a population of 703 PD patients and 695 unrelated healthy controls from southern Spain. Thirteen variants were found, twelve of them observed only in controls or in patients and controls, and one (c.190A>G) observed only in one patient. Subsequent analysis of this variant indicates that probably it is not pathogenic. In addition, we found a variation in the 3'-UTR (rs183551373) and related with the miRNA hsa-miR-4299 but it was observed only in healthy controls. Our results suggest that variants in TMEM230 gene are not associated with the development of PD.
| S-EPMC5957438 | biostudies-literature
Project description:Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.
| S-EPMC5812479 | biostudies-literature
Project description:TMEM230 is a newly identified Parkinson's disease (PD) gene encoding a transmembrane protein whose cellular and pathogenic roles remain largely unknown. Here, we demonstrate that loss of TMEM230 disrupts retromer cargo CI-M6PR (cation-independent mannose 6-phosphate receptor) trafficking and autophagic cargo degradation rates. TMEM230 depletion further inhibits extracellular secretion of the autophagic cargo p62 and immature lysosomal hydrolases in Golgi-derived vesicles leading to their intracellular accumulation, and is specifically mediated by loss of the small GTPase Rab8a. Importantly, PD-linked TMEM230 variants also induce retromer mislocalization, defective cargo trafficking, and impaired autophagy. Finally, we show that knockdown of another PD gene, LRRK2, which phosphorylates Rab8a, similarly impairs retromer trafficking, secretory autophagy and Golgi-derived vesicle secretion, thus demonstrating converging roles of two PD genes TMEM230 and LRRK2 on Rab8a function, and suggesting that retromer and secretory dysfunction play an important role in PD pathogenesis.
| S-EPMC6251589 | biostudies-literature
Project description:BackgroundTo date, variants in the GBA gene represent the most frequent large-effect genetic factor associated with Parkinson's disease (PD). However, the reason why individuals with the same GBA variant may or may not develop neurodegeneration and PD is still unclear.ObjectivesTherefore, we evaluated the contribution of rare variants in genes responsible for lysosomal storage disorders (LSDs) to GBA-PD risk, comparing the burden of deleterious variants in LSD genes in PD patients versus asymptomatic subjects, all carriers of deleterious variants in GBA.MethodsWe used a custom next-generation sequencing panel, including 50 LSD genes, to screen 305 patients and 207 controls (discovery cohort). Replication and meta-analysis were performed in two replication cohorts of GBA-variant carriers, of 250 patients and 287 controls, for whom exome or genome data were available.ResultsStatistical analysis in the discovery cohort revealed a significantly increased burden of deleterious variants in LSD genes in patients (P = 0.0029). Moreover, our analyses evidenced that the two strongest modifiers of GBA penetrance are a second variation in GBA (5.6% vs. 1.4%, P = 0.023) and variants in genes causing mucopolysaccharidoses (6.9% vs. 1%, P = 0.0020). These results were confirmed in the meta-analysis, where we observed pooled odds ratios of 1.42 (95% confidence interval [CI] = 1.10-1.83, P = 0.0063), 4.36 (95% CI = 2.02-9.45, P = 0.00019), and 1.83 (95% CI = 1.04-3.22, P = 0.038) for variants in LSD genes, GBA, and mucopolysaccharidosis genes, respectively.ConclusionThe identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
| S-EPMC9310717 | biostudies-literature
Project description:Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice striata, and in the latter we could also observe a consistent reduction in DNA methylation at gene promoter and an increase in histone H3 acetylation at lysine 9. Of particular relevance in clinical samples, we also observed higher levels in the receptor gene expression in younger subjects, as well as in those with less years from disease onset, and less severe disease according to clinical scores. In conclusion, the present findings provide further evidence of the relevant role of A2AR in PD and, based on the clinical data, highlight its potential role as disease biomarker for PD especially at the initial stages of disease development. Furthermore, our preclinical results also suggest selective epigenetic mechanisms targeting gene promoter as tool for the development of new treatments.
| S-EPMC6635589 | biostudies-literature
Project description:Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.
| S-EPMC6888719 | biostudies-literature
Project description:Parkinson's disease (PD) is common, age-dependent neurodegenerative disorder caused by a severe loss of the nigrostriatal dopaminergic neurons. Given the projected increase in the number of people with PD over the coming decades, interventions aimed at minimizing morbidity and improve quality of life are crucial. There is currently no fully proven pharmacological therapy that can modify or slow the disease progression. Physical activity (PA) can complement pharmacological therapy to manage the inherent decline associated with the disease. The evidence indicates that upregulation of neurotrophins and nerve growth factors are potentially critical mediators of the beneficial effects associated with PA. Accumulating evidence suggests that patients with PD might benefit from PA in a number of ways, from general improvements in health to disease-specific effects and potentially, disease-modifying effects. Various forms of PA that have shown beneficial effects in PD include - aerobic exercises, treadmill training, dancing, traditional Chinese exercise, yoga, and resistance training. In this review, we explored available research that addresses the impact of exercise and PA on PD. The original articles with randomized control trials, prospective cohort studies, longitudinal studies, meta-analysis, and relevant review articles from 2005 to 2017 were selected for the present review. Many gaps remain in our understanding of the most effective exercise intervention for PD symptoms, the mechanisms underlying exercise-induced changes and the best way to monitor response to therapy. However, available research suggests that exercise is a promising, cost-effective, and low-risk intervention to improve both motor and nonmotor symptoms in patients with PD. Thus, PA should be prescribed and encouraged in all PD patients.
| S-EPMC6238554 | biostudies-other