Role of the TOMM40 poly-T variant in the pathogenesis of Alzheimer's disease

描述(由申请人提供)：我们已经证明，TOMM40基因的多态多态T变异与迟发性阿尔茨海默病(AD)的发病年龄有很强的相关性。对于发生AD的APOE E3/4患者，那些与APOE E3连锁的长多核苷酸重复序列的患者比那些与APOE E3连锁的较短的多T重复序列患者平均早7年患上AD。我们在一个不同的人群中重复了这一发现。在ApoE E3/E3纯合子中，多T变异体的长度与灰质密度之间也存在显著的相关性，这与ApoE e4无关。TOMM40与APOE基因连锁不平衡，编码外线粒体膜蛋白转位酶。我们的中心假设是，多T区控制TOMM40和APOE在大脑中的表达，从而调节这些蛋白参与的途径。我们将在基因组、遗传和生化水平上检验这一假说。我们将准确地识别长、短和祖先的PolyT束，并将AD的发病年龄和AD风险与这些等位基因相关联。我们将测试我们的工作模型，即多T束通过测量快速尸检的人脑样本中APOE和TOMM40的mRNA和蛋白水平来调节TOMM40和APOE的表达，并将这些变化与不同大脑区域对AD相关损伤的易感性相关联。我们还将构建两个TOMM40-APOE连锁不平衡区的人源化小鼠模型，这将允许对这些基因的表达调控进行更详细的、基于机制的研究。我们将小鼠TOMM4-APOE连锁不平衡区与同源人区互换。这两个模型都将使人类APOE E3纯合，从而消除APOE e4可能的混杂效应，我们将使一个纯合子用于短多态T多态，而我们将使另一个纯合子用于长多聚T变体。成功地实现这些目标将促进我们对阿尔茨海默病遗传危险因素的分子机制的理解，并将为开发有效的晚发性阿尔茨海默病预防治疗提供有价值的途径。

DESCRIPTION (provided by applicant): We have demonstrated that there is a strong association between polymorphic poly-T variant of TOMM40 and the age of onset of late-onset Alzheimer's disease (AD). For APOE e3/4 patients who develop AD, those with long poly-T repeats linked to APOE e3 developed AD on average 7 years earlier than those with shorter poly-T polymorphisms linked to APOE e3. We have replicated this finding in a distinct population. In APOE e3/e3 homozygotes there is also a significant correlation between the length of the poly-T variant and grey matter density, which is independent of APOE e4. TOMM40 is in linkage disequilibrium with APOE and encodes the protein Translocase of the Outer Mitochondrial Membrane. Our central hypothesis is that the poly-T tract controls expression of TOMM40 and APOE in brain, and thus regulates the pathways in which these proteins participate. We will test this hypothesis at the genomic, genetic and biochemical levels. We will precisely identify the long, short and the ancestral poly-T tracts, and correlate the age o onset of AD and AD risk to these alleles. We will test our working model that the poly-T tract regulates TOMM40 and APOE expression by measuring APOE and TOMM40 mRNA and protein levels in rapidly autopsied human brain samples, and correlate these changes with susceptibility to AD-related damage across different brain regions. We will also construct two humanized mouse models of the TOMM40-APOE linkage disequilibrium region, that will permit more detailed, mechanism-based studies of the regulation of expression of these genes. We will exchange the mouse TOMM4-APOE linkage disequilibrium region with the homologous human region. Both models will be made homozygous for human APOE e3, thus eliminating possible confounding effects of APOE e4, and we will make one homozygous for the short poly-T polymorphism while we will make the other homozygous for the long poly-T variant. Successfully fulfilling these aims will advance our understanding of the molecular mechanisms underlying the genetic risk factors in AD and will provide valuable pathways for developing an effective preventive therapy for late-onset Alzheimer's disease.