Genetic determinants of a synuclein and tau

项目2将使用中间病理表型来探索与正在进行的遗传变异的关联- 麻痹性核上性麻痹（PSP）和路易体病（LBD）。这些结果将提供深入了解分子 帕金森病的基础我们将使用MAPT，以及非M（4PT单核苷酸多聚体， 来自全基因组关联研究（GWAS）的单核苷酸多态性（SNP）。目标1.产生中间病理 PSP的表型。我们将使用数字成像来测量上级额回、运动皮层， 杏仁核、尾状核、脑桥基底和小脑齿状核;小胶质细胞增生伴IBA-1免疫组化， 丘脑底核和黑质化学。我们将记录临床表型（性别、诊断、年龄）， 发病、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的半定量评分、生化特征- 从尾状核的蛋白质印迹中分离tau蛋白，并从尾状核中构建估计的潜在性状变量。 半定量病变评分。目标二。评估中间病理表型与基因 PSP的变体。我们将关注在PSP中实现p<1x 10 - 1的2个AMPT SNP和23个非MAPT SNP。 GWAS。每个SNP将在700多例PSP病例中针对5种原发性病理性phe进行相关性检测。 无名氏我们假设中间病理表型，大样本量和靶向SNP将 在识别PSP遗传风险变异的机制方面是强大的。目标3。生成中间病理学- LBD的IC表型。我们将测量额中回、上级颞叶和颞叶的a-突触核蛋白、A3和tau蛋白的负荷。 口回、杏仁核和壳核;壳核的酪氨酸羟化酶免疫组织化学; 黑质和Meynert基底核。我们将记录临床表型（如PSP，但也包括痴呆 和/或帕金森综合征）、病理表型（脑干、过渡或弥漫性LBD;纯LBD vs.混合LBD） 以及5个皮质区和杏仁核的路易体计数。我们将评估潜在的特质变量- 如目标1中所述，对LB、斑块和缠结进行半定量评分。目标4。评估关联性- 介导来自PD GWAS的基因变体的病理表型。SNP将被识别为来自 验尸官GWAS我们将专注于2个MAPT SNPS和23个非/W>！P7 SNP达到p<1x 10 '（R）。每个 将在700多例LBD病例中检测SNP与9种中间表型的相关性。最后，g- 大量PSP和LBD大脑的遗传学和表型数据不仅提供了 洞察力，但也是Udall中心合作者和其他人的资源。

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.