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: 8739685
• 负责人: Ornit Chiba-Falek
• 金额: $ 35.97万
• 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/8739685
• 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; 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标志，称为人类“突触核酸疾病”，是在死后脑检查后的细胞内蛋白质聚集体，Lewy身体（LB）的存在。 α-核蛋白蛋白是LB的主要成分。帕金森氏病（PD）是人类“突触性疾病”的原型，已被广泛研究。全基因组关联研究（GWAS）已将α-突触核蛋白（SNCA）基因牵涉到PD发病机理的核心参与者。细胞培养和动物模型的几项研究报告说，野生型SNCA的表达过多可能是有毒的，可能导致细胞死亡。此外，以前我们记录了散发性PD患者的SNCA表达升高。描述SNCA表达调控的基础的分子机制以及对这种调节的任何遗传变异性，对于理解非常重要 LB相关疾病的发病机理。该提案的总体目标是了解控制SNCA表达的遗传因素。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泛的LB疾病相关，重点是与Lewy Bodies（DLB）（DLB）（DLB）和LB呈现的尸检病例和阿尔茨海默氏病（AD）中的LB表现。为了实现我们的目标，我们将解决以下特定目的：1。确定SNCA变体是否与LB神经病理学相关，在神经退行性疾病中，特别是在AD和DLB中。 2。确定SNCA基因座的遗传变异是否会在神经病理学正常和受LB影响的人的大脑的不同解剖区域中改变SNCA-MRNA和蛋白质表达； 3。探索SNCA基因座内的深度候选子区域，以识别有助于发展LB病理风险的新型变体，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表达变异性遗传基础的理解以及这些变体与LB病理学的一般相关性。此外，拟议的研究将增强我们对有助于LB疾病在内的遗传危险因素和分子机制的理解，并为开发针对SNCA表达水平的疗法提供有价值的信息。