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

基本信息

批准号：
8320241
负责人：
RICHARD H MYERS
金额：
$ 46.71万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/8320241
关键词：
Affect Age Age of Onset Alcohol consumption Alleles Alternative Splicing Alzheimer&apos 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

项目摘要

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.

描述（由申请人提供）：我们针对家族性帕金森氏病（PD）的基因组广泛协会研究（GWAS）是第一个识别与PD风险有关的细胞周期蛋白G相关激酶（GAK）基因。现在，GAK基因中PD风险增加的GAK基因中RS1564282 SNP的Meta-PD GWAS分析现已显示出明确的全基因组效应（至少P = 4.8 x 10-15）。值得注意的是，这种效果在家族性PD中似乎特别强。最近，我们发表了GAK与1-核蛋白毒性有关。来自PD和控制大脑的验尸后皮质的微阵列表达分析发现，rs1564282的显着关联与1-触突蛋白表达的增加，这对疾病发病机理有影响。此外，GAK的敲低显着增加了PD神经元细胞模型中的1-核蛋白毒性。 GAK通过与组织蛋白酶-D（CTSD）的相互作用在内吞作用中起关键作用，这是参与1-核蛋白降解的主要溶酶体酶。综上所述，这些研究暗示了GAK在PD发病机理中的新作用。由于激酶（例如GAK）是治疗干预的有吸引力的靶标，因此解决了GAK基因区域中负责任的功能变体及其对GAK表达和功能的影响有望在PD研究和治疗学方面的重要进步。该应用建议识别负责任的突变，并进一步评估其在涉及的内吞途径和PD发病机理中的作用。我们提出了一系列确定的DNA测序，RNA测序，替代剪接，基因表达和临床风险分析研究，具有重要的翻译意义。具体而言，AIM 1将通过在480个家族性PD病例中重新配置225 kb和从我们的GenEPD家族性PD队列中重新配置225 kb的功能序列变体，从而确定了该基因，从而大大增强了功能变体成功发现的可能性。 AIM 2建议在一系列大型的34个PD和29个对照大脑中执行RNA测序，为此，已经可以使用广泛的SNP基因分型和微阵列数据。 RNA-seq数据将用于研究内吞途径中GAK和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基因有关的GWA（例如SNCA，MAPT，BST1等），并对病例和对照组进行全转录组的比较。最后，AIM 3探讨了AIM 1和2中发现的携带变体和突变的PD病例的特征，并利用了基因基因和基因环境相互作用以及遗传风险分析研究中鉴定序列变体的基因分型。遗传风险分析研究在PD的风险预测和诊断方面具有重要的转化含义，以及在PD的临床试验中解释治疗反应。这些PD研究人员对GAK基因和地区具有独特的经验，并且已经掌握了进行这些确定研究所需的所有样品。