Abnormalities of cholesterol metabolism in multiple system atrophy

多系统萎缩中胆固醇代谢异常

基本信息

批准号：
10593570
负责人：
Catarina M. Quinzii
金额：
$ 24.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593570
关键词：
Adult Affect Anabolism Astrocytes Ataxia Biochemical Biology Cell Death Cell membrane Cell model Cells Chemicals Cholesterol Cholesterol Homeostasis Coenzyme Q10 Data Defect Disease Down-Regulation Enzymes Equilibrium Etiology Functional disorder Genes Homeostasis Human Impairment Induced pluripotent stem cell derived neurons Link Lipids Lipoproteins Measures Membrane Membrane Microdomains Metabolic Pathway Mitochondria Molecular Morphology Multiple System Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Oxidative Phosphorylation Pathogenesis Pathogenicity Pathway interactions Patients Production Proteins Publishing Regulation Reporting Role Supplementation Transferase Ubiquinone Up-Regulation Yeasts cholesterol biosynthesis cofactor extracellular hydroxybenzoate membrane activity mevalonate new therapeutic target novel overexpression prevent therapeutic target trafficking ultra high resolution virtual

项目摘要

Summary Multiple system atrophy, or MSA, is the most common cause of adult-onset neurodegenerative ataxia, and so far, no disease-modifying therapy has been developed. One of the reasons for this lack of therapy is that the etiology of MSA remains unclear, though several possible mechanisms have been proposed. Defects in the synthesis and levels of Coenzyme Q (ubiquinone, CoQ), a lipophillic molecule present in virtually all cell membranes, represent a common phenomenon in MSA, with or without mutations in the COQ2 gene, which encodes 4-para-hydroxybenzoate polyprenyl transferase, the second enzyme involved in CoQ10 biosynthesis. The essential role of CoQ in mitochondrial oxidative phosphorylation has been explored in the context of neurodegenerative disease such as MSA. However, other aspects of CoQ biology, such as its role in the regulation of cholesterol metabolism, have not been investigated. Cholesterol homeostasis is maintained in the cell by a tightly-regulated balance between its de novo synthesis, and its internalization from extracellular lipoproteins. Alterations in this balance result in neuronal dysfunction. The biosynthesis of cholesterol and CoQ are two co-regulated branches of the mevalonate pathway. As such, stimulation of cholesterol biosynthesis also results in increases in CoQ production; thus, decrease in CoQ levels should result in the subsequent activation of the mevalonate pathway and the de novo synthesis of cholesterol, followed by inhibition of the internalization of extracellular cholesterol, to maintain homeostasis. We propose that defects in CoQ biosynthesis induce cell dysfunction by alterations in cholesterol homeostasis via sustained downregulation of cholesterol internalization (AIM 1). Our published data showed that decrease in the internalization of cholesterol, but not its synthesis, results in defects in the formation of mitochondria-associated ER membranes (MAM) domains, an ER lipid-raft involved in the modulation of multiple metabolic pathways, including the regulation of lipid homeostasis. Notably, defects in the formation of MAM domains have been observed in neurodegenerative diseases such as AD, PD and ALS. Recently, CoQ synthesis has been shown to be regulated at MAM domains in yeast. However, whether this is also the case in human cells it not known. Based on our preliminary data, we propose a novel mechanism by which CoQ defects, via inhibition of cholesterol internalization, impair the formation of MAM domains and the inhibition of the activities localized in this domain (AIM 2). Our results will elucidate the interplay between CoQ, cholesterol metabolism and MAM function, and its contribution to neuronal demise in MSA, and other neurodegenerative diseases.

概括多系统萎缩（MSA）是成人发病的神经退行性共济失调的最常见原因，因此迄今为止，尚未开发出疾病缓解疗法。缺乏治疗的原因之一是尽管已经提出了几种可能的机制，但 MSA 的病因仍不清楚。缺陷在辅酶 Q（泛醌，CoQ）的合成和水平，这是一种几乎存在于所有细胞中的亲脂性分子膜，代表 MSA 中的常见现象，无论有或没有 COQ2 基因突变，编码 4-对羟基苯甲酸聚异戊二烯基转移酶，这是参与 CoQ10 生物合成的第二种酶。 CoQ 在线粒体氧化磷酸化中的重要作用已在以下背景下进行了探索：神经退行性疾病，如 MSA。然而，CoQ 生物学的其他方面，例如它在胆固醇代谢的调节，尚未研究。细胞内的胆固醇稳态是通过其从头合成、及其从细胞外脂蛋白的内化。这种平衡的改变会导致神经元功能障碍。胆固醇和 CoQ 的生物合成是甲羟戊酸途径的两个共同调节的分支。像这样，刺激胆固醇生物合成也会导致 CoQ 产量增加；因此，CoQ 水平下降应导致甲羟戊酸途径的随后激活和胆固醇的从头合成，其次是抑制细胞外胆固醇的内化，维持体内平衡。我们建议 CoQ 生物合成缺陷通过持续改变胆固醇稳态来诱导细胞功能障碍胆固醇内化下调（AIM 1）。我们发表的数据表明，胆固醇内化的减少，而不是其合成的减少，会导致线粒体相关内质网膜（MAM）结构域（一种参与内质网脂筏的线粒体相关内质网膜）形成缺陷多种代谢途径的调节，包括脂质稳态的调节。值得注意的是，缺陷在 AD、PD 和 ALS 等神经退行性疾病中观察到了 MAM 结构域的形成。最近，CoQ 合成已被证明在酵母中的 MAM 结构域受到调节。然而，这是否是人类细胞中的情况也是如此，目前尚不清楚。根据我们的初步数据，我们提出了一种 CoQ 缺陷的新机制，通过抑制胆固醇内化，损害 MAM 结构域的形成并抑制局部活动该域（AIM 2）。我们的结果将阐明 CoQ、胆固醇代谢和 MAM 功能之间的相互作用及其导致 MSA 和其他神经退行性疾病中神经元死亡的因素。