Lewy body neuropathologies and SNCA gene: variants expression and splicing

描述(由申请人提供)： 一组神经退行性疾病的神经病理学特征是在尸检中发现细胞内蛋白聚集体--路易小体(LB)，这种疾病被称为人类“联核病”。α-突触核蛋白是LB的主要成分。帕金森氏病(Parkinson‘s Disease，PD)是人类“共核病”的原型，已被广泛研究。全基因组关联研究表明，α-突触核蛋白(SNCA)基因在帕金森病的发病机制中起核心作用。在细胞培养和动物模型中的几项研究报告称，过度表达野生型SNCA可能是有毒的，并可能导致细胞死亡。此外，先前我们发现散发性帕金森病患者SNCA表达升高。描述SNCA表达调控的分子机制，以及影响这一调控的任何遗传变异，对于理解这一点非常重要。 肝病相关疾病的发病机制。这项建议的首要目标是了解控制SNCA表达的遗传因素。我们将进一步调查SNCA基因座的任何遗传变异和/或基因表达的变化是否与广泛的LB病相关，重点是尸检确认的路易体痴呆(DLB)病例和阿尔茨海默病(AD)的LB型表现。为了实现我们的目标，我们将解决以下具体目标：1.确定SNCA变异体是否与神经退行性疾病，特别是AD和DLB的LB神经病理有关。2.确定SNCA基因座的遗传变异性是否改变了神经病理正常和Lb病变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，以找出与Lb病理发生风险有关的新的变异，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病理的一般相关性的理解。此外，拟议的研究将加深我们对包括PD在内的LB病的遗传风险因素和分子机制的了解，并为开发针对SNCA表达水平的治疗提供有价值的信息。

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.