Abnormalities of cholesterol metabolism in multiple system atrophy

多系统萎缩中胆固醇代谢异常

• 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
• 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

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.

总结 多系统萎缩（MSA）是成人发作的神经退行性共济失调的最常见原因，因此 迄今为止还没有开发出改善疾病的治疗方法。缺乏治疗的原因之一是， MSA的病因仍不清楚，尽管已经提出了几种可能的机制。缺陷 辅酶Q（泛醌，CoQ），一种存在于几乎所有细胞中亲脂分子的合成和水平 膜，代表MSA中的常见现象，有或没有COQ 2基因突变， 编码4-对羟基苯甲酸聚异戊二烯转移酶，这是辅酶Q10生物合成中涉及的第二种酶。 辅酶Q在线粒体氧化磷酸化中的重要作用已经在以下背景下进行了探索： 神经退行性疾病，例如MSA。然而，辅酶Q生物学的其他方面，如其在 胆固醇代谢的调节尚未研究。 胆固醇的体内平衡通过其从头合成， 以及其从细胞外脂蛋白的内化。这种平衡的改变导致神经元功能障碍。 胆固醇和辅酶Q的生物合成是甲羟戊酸途径的两个共调节分支。因此，在本发明的一个方面， 胆固醇生物合成的刺激也导致辅酶Q产生的增加;因此，辅酶Q水平降低 应该导致甲羟戊酸途径的随后激活和胆固醇的从头合成， 随后抑制细胞外胆固醇的内化以维持体内平衡。我们提出 辅酶Q生物合成的缺陷通过持续的胆固醇稳态改变诱导细胞功能障碍， 下调胆固醇内化（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，导致 在与ER相关的ER膜（MAM）结构域的形成中存在缺陷， 多种代谢途径的调节，包括脂质稳态的调节。值得注意的是， 在神经变性疾病如AD、PD和ALS中已经观察到MAM结构域的形成。 最近，辅酶Q的合成已被证明是在酵母中的MAM结构域的调节。然而，无论这是 人类细胞中的情况也是未知的。 基于我们的初步数据，我们提出了一种新的机制，通过抑制辅酶Q缺陷， 胆固醇内化，损害MAM结构域的形成和抑制活动定位在 此域（AIM 2）。 我们的研究结果将阐明辅酶Q，胆固醇代谢和MAM功能之间的相互作用， 在MSA和其他神经退行性疾病中对神经元死亡的贡献。