Genetic determinants of a synuclein and tau

突触核蛋白和 tau 蛋白的遗传决定因素

• 批准号: 8909208
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 17.44万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909208
• 关键词: Age; Age of Onset; Alzheimer' s Disease; Amygdaloid structure; Area; Autopsy; Basal Nucleus of Meynert; Basis pontis; Biochemical; Biological Markers; Brain; Brain Stem; Cessation of life; Clinical; Collaborations; Data; Databases; Dementia; Dentate nucleus; Diagnosis; Diffuse Lewy Body Disease; Frontal gyrus; Funding; Genes; Genetic; Genetic Determinism; Genetic Risk; Grouping; Haplotypes; Image Analysis; Immunohistochemistry; Individual; Lead; Lesion; Lewy Bodies; Lewy Body Disease; Measures; Mediating; Meta-Analysis; Molecular; Molecular Biology; Motor Cortex; Neurofibrillary Tangles; Neurons; Paralysed; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Phenotype; Population; Progressive Supranuclear Palsy; Research; Resources; Risk Factors; Sample Size; Single Nucleotide Polymorphism; Staging; Structure of subthalamic nucleus; Structure of superior frontal gyrus; Substantia nigra structure; Superior temporal gyrus; Tauopathies; Testing; Tyrosine 3-Monooxygenase; Validation; Variant; Western Blotting; accurate diagnosis; alpha synuclein; base; caudate nucleus; clinical phenotype; density; digital; falls; frontal lobe; genetic information; genetic variant; genome wide association study; hindbrain; illness length; inclusion criteria; insight; novel; protein aggregate; putamen; risk variant; sex; synucleinopathy; tau Proteins; trait

Project 2 will use intemnediate pathologic phenotypes to explore associations with genetic variants in progres- sive supranuclear palsy (PSP) and Lewy body disease (LBD). The results will provide insights into the molecular underpinnings of Parkinsonian disorders. We will use MAPT, as well as non-M(4PT single nucleotide polymor- phisms (SNPs) from genome-wide association studies (GWAS). Aim 1. Generate intermediate pathologic phenotypes for PSP. We will measure burden of tau using digital imaging in superior frontal gyrus, motor cortex, amygdala, caudate nucleus, pontine base and cerebellar dentate nucleus; microgliosis with IBA-1 immunohisto- chemistry in subthalamic nucleus and substantia nigra. We will record clinical phenotypes (sex, diagnosis, age at onset, age at death, disease duration), pathologic groupings (typical PSP vs. atypical PSP; pure PSP vs. mixed PSP), semi-quantitative scores of neuronal, astrocytic and oligodendroglial lesion density, biochemical characte- rization of tau from Western blots of caudate nucleus, and estimated latent trait variables constructed from the semiquantitative lesion scores. Aim 2. Assess association of intermediate pathologic phenotypes with gene variants in PSP. We will focus on 2 AMPT SNPs and 23 non-MAPT SNPs that achieved p<1x10'^ in the PSP GWAS. Each SNP will be tested for association in more than 700 PSP cases against 5 primary pathologic phe- notypes. We hypothesize that intermediate pathologic phenotypes, a large sample size and targeted SNPs will be powerful in identifying mechanisms of genetic risk variants in PSP. Aim 3. Generate intermediate patholog- ic phenotypes for LBD. We will measure burden of a-synuclein, A3, and tau in mid-frontal gyrus, superior tem- poral gyrus, amygdala and putamen; tyrosine hydroxylase immunohistochemistry of putamen; and microgliosis in substantia nigra and basal nucleus of Meynert. We will record clinical phenotypes (as for PSP, but also dementia and/or Parkinsonism), pathological phenotypes (brainstem, transitional, or diffuse LBD; pure LBD vs. mixed LBD) as well as Lewy body counts in 5 cortical areas and the amygdala. We will estimate latent trait variables underly- ing the semiquantitative scores of LBs, plaques and tangles as in Aim 1. Aim 4. Assess association of inter- mediate pathologic phenotypes with gene variants from PD GWAS. SNPs will be identified as top hits from the autopsy PD GWAS. We will focus on 2 MAPT SNPS and 23 non-/W>!\P7SNPs that achieved p<1x10'(R). Each SNP will be tested for association with 9 intermediate phenotypes in more than 700 LBD cases. Ultimately, ge- netic and phenotypic data on a large number of PSP and LBD brains will not only provide mechanistic insight, but also be a resource for Udall Center collaborators and for others.

项目 2 将使用中间病理表型来探索与进展中遗传变异的关联。 严重核上性麻痹（PSP）和路易体病（LBD）。结果将为分子生物学提供深入的见解 帕金森病的基础。我们将使用 MAPT，以及非 M(4PT 单核苷酸多态性) 来自全基因组关联研究 (GWAS) 的 phism (SNP)。目标 1. 生成中间病理 PSP 的表型。我们将使用数字成像测量额上回、运动皮层、 杏仁核、尾状核、脑桥基底和小脑齿状核； IBA-1 免疫组化小胶质细胞增生 丘脑底核和黑质的化学。我们将记录临床表型（性别、诊断、年龄） 发病年龄、死​​亡年龄、病程）、病理分组（典型 PSP 与非典型 PSP；纯 PSP 与混合 PSP） PSP），神经元、星形胶质细胞和少突胶质细胞病变密度、生化特征的半定量评分 从尾状核的蛋白质印迹中 tau 蛋白的化，并估计潜在性状变量 半定量损伤评分。目标 2. 评估中间病理表型与基因的关联 PSP 中的变体。我们将重点关注在 PSP 中实现 p<1x10'^ 的 2 个 AMPT SNP 和 23 个非 MAPT SNP GWAS。每个 SNP 将在 700 多个 PSP 病例中针对 5 种原发性病理现象进行关联测试。 没有类型。我们假设中间病理表型、大样本量和靶向 SNP 将 在识别 PSP 遗传风险变异机制方面具有强大作用。目标 3. 生成中间病理学- LBD 的 ic 表型。我们将测量额中回、上丘脑中 α-突触核蛋白、A3 和 tau 蛋白的负担 门回、杏仁核和壳核；壳核酪氨酸羟化酶免疫组化；和小胶质细胞增生 黑质和 Meynert 基底核。我们将记录临床表型（对于 PSP，还有痴呆症） 和/或帕金森病）、病理表型（脑干、过渡性或弥漫性 LBD；纯 LBD 与混合 LBD） 以及 5 个皮质区域和杏仁核的路易体计数。我们将估计潜在的特质变量—— 目标 1 中的 LB、斑块和缠结的半定量评分。 目标 4. 评估间的关联 通过 PD GWAS 的基因变异介导病理表型。 SNP 将被确定为热门命中 尸检 PD GWAS。我们将重点关注实现 p<1x10'(R) 的 2 个 MAPT SNPS 和 23 个非 /W>!\P7SNP。每个 将在 700 多个 LBD 病例中测试 SNP 与 9 种中间表型的关联。最终，格- 大量 PSP 和 LBD 大脑的网络和表型数据不仅可以提供机制 洞察力，同时也成为尤德尔中心合作者和其他人的资源。