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）： 一组被称为人类“突触核蛋白病”的神经退行性疾病的神经病理学标志是在死后脑部检查中存在细胞内蛋白质聚集体，路易体（LB）。 α-突触核蛋白是 LB 的主要成分。帕金森病 (PD) 是人类“突触核蛋白病”的原型，已得到广泛研究。全基因组关联研究 (GWAS) 表明 α-突触核蛋白 (SNCA) 基因在 PD 发病机制中发挥着核心作用。多项细胞培养物和动物模型研究报告称，野生型 SNCA 的过度表达可能具有毒性，并可能导致细胞死亡。此外，之前我们记录了散发性 PD 患者中 SNCA 表达升高。描述 SNCA 表达调控的分子机制以及影响这种调控的任何遗传变异对于理解这一点非常重要 LB相关疾病的发病机制。该提案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 位点的任何遗传变异和/或基因表达的变化是否与广谱 LB 疾病相关，重点关注尸检确诊的路易体痴呆 (DLB) 病例和阿尔茨海默病中的 LB 表现。广告）。为了实现我们的目标，我们将实现以下具体目标： 1. 确定 SNCA 变异是否与神经退行性疾病（特别是 AD 和 DLB）中的 LB 神经病理学相关。 2.确定SNCA位点的遗传变异是否改变神经病理学正常和LB影响的人脑不同解剖区域的SNCA-mRNA和蛋白表达； 3. 深入探索 SNCA 基因座内的候选亚区域，以确定导致 LB 病理学风险的新变异，并评估它们对 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包括 PD 在内的 LB 疾病的遗传风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。