Genetic determinants of a synuclein and tau

项目2将使用间接病理表型来探索与进展中的遗传变异的关联。 进行性核上性麻痹(PSP)和路易体病(LBD)。这些结果将提供对分子的洞察。 帕金森氏症的基础。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的单核苷酸多态性(SNPs)。目标1.生成中间病理 PSP的表型。我们将使用数字成像技术在额叶上回、运动皮质 杏仁核、尾状核、桥基和小脑齿状核；小胶质细胞增多症与IBA-1免疫组织化学染色。 丘脑底核和黑质的化学成分。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；单纯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Western blotts中获得tau的RIZ化，并估计从 半定量损伤评分。目的2.评估中间病理表型与基因的相关性 PSP中的变种。我们将重点关注在PSP中获得P&lt；1x10‘^的2个AMPT SNP和23个非MAPT SNP GWARD。每个SNP将在700多例PSP病例中与5种原发病理PHE进行关联测试。 无类型。我们假设中间病理表型、大样本和靶向SNPs将 在识别PSP的遗传风险变异机制方面具有很强的能力。目标3.生成中间病理图- LBD的IC表型。我们将测定额中回的α-突触核蛋白、A3和tau的负荷。 门回、杏仁核和壳核；壳核的酪氨酸羟基酶免疫组织化学； Meynert黑质和基底核。我们将记录临床表型(如PSP，但也包括痴呆 和/或帕金森病)，病理表型(脑干、过渡性或弥漫性LBD；单纯LBD与混合型LBD) 以及5个皮质区和杏仁核的路易小体计数。我们将低估潜在的特质变量- 目标1.目标4.评估LBS、斑块和缠结之间的关联性 用帕金森病患者的基因变异来调节病理表型。SNPs将被确定为来自 尸检的警员说。我们将重点关注获得p&lt；1x10‘(R)的2个MAPT SNPs和23个非/W&>！\P7SNPs。每个人 将在700多个LBD病例中测试SNP与9种中间表型的相关性。最终，GE- 大量PSP和LBD大脑的磁学和表型数据不仅提供了机械性 洞察力，但也是Udall中心合作者和其他人的资源。 相关性(请参阅实例)： 这个项目中提出的研究将收集大量详细的病理和分子信息。 死于帕金森氏病(PD)或进行性上呼吸道疾病的人的大脑数量- 李尔麻痹(PSP)。这些信息将在同一个大脑上收集到详细的基因信息来去破译 确定哪些基因负责在这些大脑中发现的病理变化。这些研究将 从而更好地了解参与帕金森病和PSP的基因。

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. RELEVANCE (See Instmctions): The research proposed in this project will collect detailed pathologic and molecular information on a large number of brains from individuals who died with either Parkinson's disease (PD) or progressive supranuc- lear palsy (PSP). This information will be to detailed genetic information collected on the same brain to de- termine which genes are responsible for the pathologic changes found in these brains. These studies will lead to a better understanding of the genes involved in PD and PSP.