Mechanistic Basis of the mtDNA Haplogroup J-Alzheimer's Disease Association

项目摘要 广泛的研究将线粒体与阿尔茨海默病（AD）联系起来，但线粒体如何导致AD 风险或进展仍未确定。在这里，我们建立在新的和令人信服的数据，表明 线粒体DNA（mtDNA）单倍型组J在AD患者中出现的频率较高。这一发现表明， 线粒体独立地导致AD，并且特别出乎意料的是，增加的单倍型群J 频率矛盾地也发生在最老的老人。四种特异性单倍群J定义多态性 三个位于调节mtDNA复制的mtDNA控制区， 第四个是非同义ND 5变体。这些变体一起旅行，目前我们 不能判断是否控制区变异，蛋白质编码变异，或组合有助于AD 风险为了解决这个问题，并获得新的AD机制的见解，我们提出了一个协同的两个目标，基准和- 床边的方法，将这些遗传协会扩展到功能协会。在目标1中，我们使用 细胞质杂种（cybrid）细胞系，以确定单倍群J变体如何影响线粒体功能， 完整在目标2中，我们使用临床生物标本和生物标志物数据进一步探索单倍型群J，AD， 和老化的联系因此，除了推进我们对AD的理解外，我们对AD的机制分析 单倍群J效应也将告知线粒体生物学如何与衰老相关。这些研究将提供 深入了解导致AD和衰老收敛但偶尔也会发散的机制。

PROJECT SUMMARY Extensive research ties mitochondria to Alzheimer's disease (AD), but how mitochondria contribute to AD risk or progression remains unsettled. Here, we build on new and compelling data that indicate the mitochondrial DNA (mtDNA) haplogroup J occurs in higher frequencies in persons with AD. This finding argues mitochondria independently contribute to AD, and is particularly unexpected as increased haplogroup J frequency paradoxically also occurs in the oldest old. Four specific haplogroup J-defining polymorphisms appear to drive the association; three reside in the mtDNA control region that regulates mtDNA replication and transcription, and the fourth is a non-synonymous ND5 variant. These variants travel together and currently we cannot tell whether the control region variants, the protein-coding variant, or a combination contributes to AD risk. To resolve this and gain new AD mechanistic insight, we propose a synergistic two-aim, bench-and- bedside approach that will extend these genetic associations to functional associations. In Aim 1, we use cytoplasmic hybrid (cybrid) cell lines to define how the haplogroup J variants affect mitochondrial function and integrity. In Aim 2, we use clinical biospecimen and biomarker data to further explore the haplogroup J, AD, and aging nexus. Thus, in addition to advancing our understanding of AD, our mechanistic analysis of haplogroup J effects will also inform how mitochondrial biology relates to aging. These studies will provide insight into mechanisms that cause AD and aging to converge, but also occasionally diverge.