Characterization of the role of cyclin G-associated kinase in Parkinson disease

细胞周期蛋白 G 相关激酶在帕金森病中作用的表征

• 批准号: 8219844
• 负责人: RICHARD H MYERS
• 金额: $ 47.16万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219844
• 关键词: Affect; Age; Age of Onset; Alcohol consumption; Alleles; Alternative Splicing; Alzheimer' s Disease; Bar Codes; Brain; Caffeine; Cathepsins; Cell model; Characteristics; Clinical; Clinical Trials; Code; DNA Resequencing; DNA Sequence; Data; Dementia; Development; Diagnosis; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Disease susceptibility; Endocytosis; Enzymes; Evaluation; Exhibits; Exons; Family history of; Family member; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Transcription; Genomics; Genotype; Hand; Health; Hereditary Disease; Individual; Length; Mental Depression; Methods; Microarray Analysis; Molecular Profiling; Mutation; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Pattern; Phase; Phosphotransferases; Play; Population; Publishing; RNA; RNA Sequences; RNA Splicing; Reading; Recording of previous events; Relative (related person); Research; Research Personnel; Resolution; Risk; Risk Factors; Role; SNP genotyping; Sampling; Series; Signal Transduction; Smoking; Spliced Genes; Technology; Testing; Therapeutic; Therapeutic Human Experimentation; Therapeutic Intervention; Tissues; Toxic effect; Transcript; Tremor; Variant; alpha synuclein; base; case control; cohort; cyclin G; disorder control; disorder risk; exome; experience; frontal lobe; gene environment interaction; genome wide association study; genome-wide; insight; interest; mind control; next generation; novel; pesticide exposure; response; segregation; synuclein

DESCRIPTION (provided by applicant): Our genome wide association study (GWAS) for familial Parkinson's disease (PD) was the first to identify the cyclin G-associated kinase (GAK) gene as associated with PD risk. Meta-PD GWAS analyses have now demonstrated an unequivocal genome-wide effect (at least P = 4.8 x 10-15) for the rs1564282 SNP in the GAK gene on increased PD risk. Notably, the effect appears to be particularly strong in familial PD. Recently, we published that GAK is associated with 1-synuclein toxicity. Microarray expression analysis of post-mortem frontal cortex from PD and control brains found a significant association of rs1564282 with increased 1- synuclein expression, which has implications for disease pathogenesis. Further, knockdown of GAK significantly increases 1-synuclein toxicity in neuronal cell models of PD. GAK plays a critical role in endocytosis through its interaction with cathepsin-D (CTSD), which is the main lysosomal enzyme involved in 1-synuclein degradation. Taken together, these studies implicate a novel role for GAK in PD pathogenesis. Since kinases, such as GAK, are attractive targets for therapeutic intervention, resolving the responsible functional variants in the GAK gene region and their effects on GAK's expression and function promise important advancements for PD research and therapeutics. This application proposes to identify the responsible mutations, and to further evaluate their role in the implicated endocytic pathway and in the pathogenesis of PD. We propose a definitive series of DNA sequencing, RNA sequencing, alternative splicing, gene expression, and clinical risk profiling studies which have important translational implications. Specifically, Aim 1 will identify functional sequence variants in the GAK region by resequencing 225 Kb in 480 familial PD cases and 96 controls from our GenePD familial PD cohort, in which the gene was identified, thus greatly enhancing the likelihood for successful discovery of functional variants. Aim 2 proposes to perform RNA-sequencing in a large well characterized series of 34 PD and 29 control brains, for which extensive SNP genotyping and microarray data are already available. The RNA-Seq data will be used to study coding sequence and expression of GAK and related genes in the endocytic pathway. RNA sequencing will also allow us to examine all the GWAS implicated PD genes (e.g. SNCA, MAPT, BST1 etc.) and to perform transcriptome-wide comparison of cases and controls. Finally, Aim 3 explores the characteristics of PD cases carrying the variants and mutations found in Aims 1 and 2 and utilizes the genotyping of identified sequence variants in gene-gene and gene- environment interaction and genetic risk profiling studies. Genetic risk profiling studies have important translational implications in risk prediction and diagnostics for PD as well as for interpretation of therapeutic response in clinical trials for PD. These PD investigators are uniquely experienced with the GAK gene and region and have already in hand all the samples needed to carry out these definitive studies. PUBLIC HEALTH RELEVANCE: This research proposes to examine the DNA sequence (genetic) and gene expression (genomic) profiles of Parkinson disease cases compared with healthy individuals to determine the role of the cyclin G-associated kinase gene in Parkinson's disease risk. The findings will provide important insight for the development of new treatments as well as in predicting and diagnosing this devastating neurodegenerative disease.

描述（由申请人提供）：我们针对家族性帕金森病 (PD) 的全基因组关联研究 (GWAS) 首次确定了细胞周期蛋白 G 相关激酶 (GAK) 基因与 PD 风险相关。 Meta-PD GWAS 分析现已证明，GAK 基因中的 rs1564282 SNP 对 PD 风险增加具有明确的全基因组效应（至少 P = 4.8 x 10-15）。值得注意的是，这种效应在家族性帕金森病中似乎特别强烈。最近，我们发表了 GAK 与 1-突触核蛋白毒性有关。对 PD 和对照大脑死后额叶皮层的微阵列表达分析发现 rs1564282 与 1-突触核蛋白表达增加显着相关，这对疾病发病机制具有影响。此外，在 PD 神经元细胞模型中，GAK 的敲低显着增加了 1-突触核蛋白的毒性。 GAK 通过与组织蛋白酶-D (CTSD) 相互作用，在内吞作用中发挥关键作用，组织蛋白酶-D 是参与 1-突触核蛋白降解的主要溶酶体酶。总而言之，这些研究表明 GAK 在 PD 发病机制中具有新的作用。由于 GAK 等激酶是治疗干预的有吸引力的靶标，因此解决 GAK 基因区域中负责的功能变异及其对 GAK 表达和功能的影响有望为 PD 研究和治疗带来重要进展。本申请旨在鉴定相关突变，并进一步评估它们在相关内吞途径和 PD 发病机制中的作用。我们提出了一系列明确的 DNA 测序、RNA 测序、选择性剪接、基因表达和临床风险分析研究，这些研究具有重要的转化意义。具体来说，目标 1 将通过对来自我们的 GenePD 家族性 PD 队列的 480 例家族性 PD 病例和 96 例对照中的 225 Kb 进行重新测序来鉴定 GAK 区域的功能序列变异，其中该基因已被识别，从而大大提高了成功发现功能变异的可能性。目标 2 提议在一个由 34 个 PD 大脑和 29 个对照大脑组成的大型系列中进行 RNA 测序，其中广泛的 SNP 基因分型和微阵列数据已经可用。 RNA-Seq数据将用于研究内吞途径中GAK及相关基因的编码序列和表达。 RNA 测序还将使我们能够检查所有与 PD 相关的 GWAS 基因（例如 SNCA、MAPT、BST1 等），并对病例和对照进行全转录组比较。最后，目标 3 探讨了携带目标 1 和 2 中发现的变异和突变的 PD 病例的特征，并在基因-基因和基因-环境相互作用以及遗传风险分析研究中利用已识别序列变异的基因分型。遗传风险分析研究对于帕金森病的风险预测和诊断以及帕金森病临床试验中治疗反应的解释具有重要的转化意义。这些 PD 研究人员对 GAK 基因和区域具有独特的经验，并且已经掌握了进行这些确定性研究所需的所有样本。 公共健康相关性：本研究旨在检查帕金森病病例与健康个体的 DNA 序列（遗传）和基因表达（基因组）谱，以确定细胞周期蛋白 G 相关激酶基因在帕金森病风险中的作用。这些发现将为新疗法的开发以及预测和诊断这种毁灭性的神经退行性疾病提供重要的见解。