Genetic and Epigenetic Regulation of COMT, a Key Moderator of Cognitive Decline

项目摘要/摘要 尽管认知功能减退(CD)和功能障碍是一种广泛而确切的巨大医疗负担， 治疗选择有限，部分原因是我们对CD的神经生物学基础了解不完全。 在包括阿尔茨海默氏症和帕金森氏病在内的各种情况下，CD的恶化通常与 儿茶酚-O-甲基转移酶(COMT)活性高。如此高的活动可能发生在 COMT基因遗传变异的后果。研究最多的COMT基因多态性rs4680是 一种A→G改变，导致COMT酶活性增加4倍。COMT分解儿茶酚胺， 是大脑皮层区域多巴胺清除的主要调节剂；它还能解毒致癌物质。 儿茶酚-雌激素。COMT有两种亚型，分别编码可溶性(S-COMT)和膜结合型 (MB-COMT)形式的酶。抑制COMT的干预可以改善认知功能， 可能是通过提升皮质多巴胺。然而，在抑制大脑中占主导地位的MB-COMT的同时， 显示认知益处，迄今没有COMT抑制剂是异构体选择性的，而对S-COMT的抑制作用增加 循环中的致癌儿茶酚-雌激素以及外周儿茶酚胺，增加对激素的敏感性 癌症风险和疼痛敏感度。虽然有强有力的证据表明COMT基因变异会改变 酶的功能，越来越多的证据也指出表观遗传COMT调节的影响，例如DNA 甲基化，调节COMT基因的表达和本体酶的活性。因此，有选择地 下调MB-COMT的表达有望成为CD的一种治疗干预手段 一系列的条件。然而，主要的机制差距仍然存在：1)目前没有有效的方法来 区分和准确测量MB-和S-COMT转录本，COMT蛋白亚型尚未被 与COMT mRNAs一起测量；2)DNA甲基化仍有待于全程完全询问 被认为调节MB-和S-COMT基因表达的区域；3)观察到的驱动代谢物 COMT的表观遗传修饰及其异构体特异性尚不清楚。因此，我们建议体外培养 研究是了解代谢物和其他表观遗传调节因子对 异构体特异性COMT在人细胞系中的表达。我们希望识别出调节COMT的化合物，以及 其潜在的表观遗传机制，这将确定CD风险的生物标记物和新的 CD的干预措施。这种未来的干预措施在应对执行功能缺陷方面可能特别有用， 这是CD的一个共同方面，包括正常老化、多发性 神经退行性疾病、精神分裂症、多动症、创伤后应激障碍、抑郁症、物质使用障碍和癌症 化疗。由于表观遗传标记是可以逆转的，因此更好地理解异构体特异性 对COMT的监管将在确定治疗和延迟这些疾病的CD的新策略方面起到变革性作用 大大减轻了他们的临床和公共卫生负担。

PROJECT SUMMARY/ ABSTRACT Although cognitive decline (CD) and impairment are widespread and exact an enormous healthcare burden, therapeutic options are limited partly due to our incomplete understanding of the neurobiological bases of CD. Across conditions, including Alzheimer's, and Parkinson's Disease, worsening CD is commonly associated with high activity of the catechol-O-methyltransferase (COMT) enzyme. Such high activity can occur as a consequence of genetic variation in the COMT gene. The most studied COMT genetic polymorphism, rs4680, is an A→G change that yields a 4-fold difference in COMT enzyme activity. COMT breaks down catecholamines, and is the primary regulator of dopamine clearance in cortical brain regions; it also detoxifies carcinogenic catechol-estrogens. There are two COMT isoforms, which encode soluble (S-COMT) and membrane bound (MB-COMT) forms of the enzyme, respectively. Interventions that inhibit COMT can improve cognitive function, presumably by elevating cortical dopamine. However, while inhibiting MB-COMT, which dominates in the brain, shows cognitive benefit, no COMT inhibitors to date are isoform selective, and inhibition of S-COMT increases circulating carcinogenic catechol-estrogens, as well as peripheral catecholamines, increasing hormone-sensitive cancer risk, and pain sensitivity, respectively. While the evidence is strong that COMT genetic variation alters enzyme function, growing evidence also points to the influence of epigenetic COMT regulation, e.g., DNA methylation, in moderating COMT gene expression and bulk enzyme activity. Thus, the ability to selectively downregulate MB-COMT expression holds tremendous promise as a therapeutic intervention for CD across a broad array of conditions. Nevertheless, major mechanistic gaps persist: 1) There currently is no efficient way to distinguish and accurately measure MB- and S-COMT transcripts, and COMT protein isoforms haven't been measured in tandem with COMT mRNAs; 2) DNA methylation remains to be completely interrogated throughout regions thought to regulate MB- and S-COMT mRNA expression; and 3) the metabolites driving observed epigenetic modification of COMT, and their isoform specificity, are unknown. We therefore propose an in vitro study as a necessary first step in understanding the effects of metabolites and other epigenetic regulators on isoform-specific COMT expression in human cell lines. We expect to identify compounds regulating COMT, and their underlying epigenetic mechanisms, which will identify both biomarkers of CD risk and targets for new interventions for CD. Such future interventions may be particularly useful in combating executive function deficits, which is an aspect of CD common to a broad array of conditions, including normal aging, multiple neurodegenerative conditions, schizophrenia, ADHD, PTSD, depression, substance use disorders, and cancer chemotherapy treatment. As epigenetic marks can be reversed, a better understanding of isoform-specific regulation of COMT will be transformative in identifying new strategies for treating and delaying CD in these populations, substantially reducing their clinical and public health burden.