Lewy body neuropathologies and SNCA gene: variants expression and splicing

路易体神经病理学和 SNCA 基因：变异表达和剪接

• 批准号: 8609956
• 负责人: Ornit Chiba-Falek
• 金额: $ 38.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609956
• 关键词: Address; Affect; Alleles; Alzheimer' s Disease; Anatomy; Animal Model; Area; Autopsy; Bioinformatics; Biological Markers; Brain; Candidate Disease Gene; Cell Culture Techniques; Cell Death; Cells; Complement; Complex; Control Groups; Data; Deposition; Development; Diagnosis; Disease; Disease susceptibility; Frequencies; Functional RNA; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Haplotypes; Health; Human; Individual; Knowledge; Lead; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Measures; Messenger RNA; Methods; Modeling; Molecular; Neurodegenerative Disorders; Neuroglia; Neurons; Observational Study; Outcome Study; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Phylogenetic Analysis; Predisposition; Proteins; Publishing; RNA Splicing; Regulation; Relative (related person); Reporter; Reporting; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; SNCA gene; Societies; Structure; System; Techniques; Testing; Transcript; Trees; Variant; alpha synuclein; base; brain tissue; case control; cohort; cost; deep sequencing; genetic association; genetic element; genetic risk factor; genetic variant; genome wide association study; interest; laser capture microdissection; mRNA Expression; neuron loss; neuropathology; novel; prevent; protein aggregate; protein expression; prototype; public health relevance; research study; segregation; synucleinopathy; therapeutic target; therapy development

DESCRIPTION (provided by applicant): A neuropathological hallmark of a group of neurodegenerative diseases, known as human 'synucleinopathies', is the presence of intracellular protein aggregates, Lewy bodies (LB), upon postmortem brain examination. The alpha-synuclein protein is a major component of LB. Parkinson's disease (PD) is the prototype of human 'synucleinopathies' and has been studied extensively. Genome-wide association studies (GWAS) have implicated the alpha-synuclein (SNCA) gene as a central player in the pathogenesis of PD. Several studies in cell-cultures and animal models reported that over expression of wild-type SNCA can be toxic and may lead to cell death. Moreover, previously we documented elevated SNCA expression in sporadic-PD patients. Describing the molecular mechanisms underlying the regulation of SNCA expression, and any genetic variability that impinges on this regulation, is highly important for understanding the pathogenesis of LB related diseases. The overarching goal of this proposal is to understand the genetic elements controlling SNCA expression. We will further investigate whether any genetic variants in SNCA locus and/or changes in gene expression are associated with a broad-spectrum of LB diseases, focusing on autopsy-confirmed cases of dementia with Lewy bodies (DLB) and LB presentation in Alzheimer's disease (AD). To accomplish our goals, we will address the following specific aims: 1. Determine whether SNCA variants are associated with LB neuropathology in neurodegenerative diseases, specifically in AD and DLB. 2. Determine whether genetic variability in the SNCA locus alters SNCA-mRNA and protein expression in different anatomic areas of neuropathologically normal and LB-affected human brains; 3. Explore in depth candidate sub-regions within the SNCA locus to identify novel variants that contribute to the risk to develop LB pathology, and evaluate their effect on SNCA expression. The fulfillment of these aims will enrich our understanding of the genetic basis of variability in SNCA expression and the general relevance of these variants to LB pathology. Moreover, the proposed studies will enhance our understanding of the genetic risk factors and molecular mechanisms that contribute to LB diseases including PD and provide valuable information for developing therapies targeting SNCA expression levels.

描述（由申请人提供）： 一组神经退行性疾病的神经病理学标志，称为人类“突触核蛋白病”，是在死后脑检查时存在细胞内蛋白质聚集体，即路易体（LB）。α-突触核蛋白是LB的主要组分。帕金森氏病（PD）是人类“突触核蛋白病”的原型，并已被广泛研究。全基因组关联研究（GWAS）表明α-突触核蛋白（SNCA）基因在PD发病机制中起着重要作用。在细胞培养物和动物模型中的几项研究报道，野生型SNCA的过度表达可能是有毒的，并可能导致细胞死亡。此外，以前我们记录了偶发性PD患者的SNCA表达升高。描述SNCA表达调控的分子机制，以及任何影响这种调控的遗传变异，对于理解SNCA的表达和遗传变异的分子机制是非常重要的。 LB相关疾病的发病机制。该建议的首要目标是了解控制SNCA表达的遗传元件。我们将进一步研究SNCA基因座中的任何遗传变异和/或基因表达的变化是否与广谱的LB疾病相关，重点关注尸检证实的路易体痴呆（DLB）和阿尔茨海默病（AD）中的LB呈递病例。为了实现我们的目标，我们将致力于以下具体目标：1。确定SNCA变体是否与神经退行性疾病中的LB神经病理学相关，特别是在AD和DLB中。2.确定SNCA基因座的遗传变异性是否会改变神经病理正常和LB影响的人脑不同解剖区域中SNCA-mRNA和蛋白质的表达; 3.深入探索SNCA基因座内的候选子区域，以鉴定导致发生LB病理风险的新变体，并评估其对SNCA表达的影响。这些目标的实现将丰富我们对SNCA表达变异的遗传基础以及这些变异与LB病理学的一般相关性的理解。此外，拟议的研究将增强我们对导致LB疾病（包括PD）的遗传风险因素和分子机制的理解，并为开发靶向SNCA表达水平的疗法提供有价值的信息。