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

项目总结 广泛的研究将线粒体与阿尔茨海默病(AD)联系在一起，但线粒体如何参与AD 风险或进展仍未确定。在这里，我们建立在新的令人信服的数据基础上，这些数据表明 线粒体DNA(MtDNA)单倍群J在AD患者中出现频率较高。这一发现认为 线粒体独立参与阿尔茨海默病的发病，单倍组J的增加尤其出乎意料 自相矛盾的是，频率也出现在年龄最大的老年人身上。四种特殊的单倍群J-定义多态 其中三个位于mtDNA控制区，调控mtDNA复制和 第四个是非同义的ND5变异体。这些变种一起旅行，目前我们 我不知道是控制区的变异、蛋白质编码的变异还是两者的结合导致了AD 风险。为了解决这一问题，并获得新的AD机制洞察力，我们提出了协同双目标，板凳和... 将这些遗传关联扩展到功能关联的床边方法。在目标1中，我们使用 细胞质杂交(胞质杂交体)细胞系，以确定单倍组J变异如何影响线粒体功能和 正直。在目标2中，我们使用临床生物样品和生物标记物数据来进一步探索单倍群J，AD， 和老化的纽带。因此，除了增进我们对AD的理解外，我们对AD的机理分析 单倍群J效应也将告诉我们线粒体生物学如何与衰老相关。这些研究将提供 对导致阿尔茨海默病和衰老的机制的洞察是一致的，但偶尔也会出现分歧。

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.