Bell Andrew S, Wagner Josephin, Rosoff Daniel B, Lohoff Falk W
Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.
Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States; Radcliffe Department of Medicine, University of Oxford, UK; NIH-Oxford-Cambridge Scholars Program, University of Oxford, UK.
Neurosci Biobehav Rev. 2023 Jun;149:105155. doi: 10.1016/j.neubiorev.2023.105155. Epub 2023 Apr 3.
The gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its protein product have been widely studied for their role in cholesterol and lipid metabolism. PCSK9 increases the rate of metabolic degradation of low-density lipoprotein receptors, preventing the diffusion of low-density lipoprotein (LDL) from plasma into cells and contributes to high lipoprotein-bound cholesterol levels in the plasma. While most research has focused on the regulation and disease relevance of PCSK9 to the cardiovascular system and lipid metabolism, there is a growing body of evidence that PCSK9 plays a crucial role in pathogenic processes in other organ systems, including the central nervous system. PCSK9's impact on the brain is not yet fully understood, though several recent studies have sought to illuminate its impact on various neurodegenerative and psychiatric disorders, as well as its connection with ischemic stroke. Cerebral PCSK9 expression is low but is highly upregulated during disease states. Among others, PCSK9 is known to play a role in neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, Alzheimer's Disease, Alcohol Use Disorder, and stroke. The PCSK9 gene contains several polymorphisms, including both gain-of-function and loss-of-function mutations which profoundly impact normal PCSK9 signaling and cholesterol metabolism. Gain-of-function mutations lead to persistent hypercholesterolemia and poor health outcomes, while loss-of-function mutations generally lead to hypocholesterolemia and may serve as a protective factor against diseases of the liver, cardiovascular system, and central nervous system. Recent genomic studies have sought to identify the end-organ effects of such mutations and continue to identify evidence of a much broader role for PCSK9 in extrahepatic organ systems. Despite this, there remain large gaps in our understanding of PCSK9, its regulation, and its effects on disease risk outside the liver. This review, which incorporates data from a wide range of scientific disciplines and experimental paradigms, is intended to describe PCSK9's role in the central nervous system as it relates to cerebral disease and neuropsychiatric disorders, and to examine the clinical potential of PCSK9 inhibitors and genetic variation in the PCSK9 gene on disease outcomes, including neurological and neuropsychiatric disease.
编码前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的基因及其蛋白产物在胆固醇和脂质代谢中的作用已得到广泛研究。PCSK9可提高低密度脂蛋白受体的代谢降解速率，阻止低密度脂蛋白（LDL）从血浆扩散到细胞中，并导致血浆中脂蛋白结合胆固醇水平升高。虽然大多数研究集中在PCSK9对心血管系统和脂质代谢的调节及与疾病的相关性上，但越来越多的证据表明，PCSK9在包括中枢神经系统在内的其他器官系统的致病过程中起着关键作用。尽管最近有几项研究试图阐明PCSK9对各种神经退行性疾病和精神疾病的影响及其与缺血性中风的联系，但其对大脑的影响尚未完全了解。脑内PCSK9表达较低，但在疾病状态下会高度上调。其中，PCSK9已知在神经发生、神经细胞分化、中枢LDL受体代谢、神经细胞凋亡、神经炎症、阿尔茨海默病、酒精使用障碍和中风中发挥作用。PCSK9基因包含多个多态性，包括功能获得性和功能丧失性突变，这些突变会深刻影响正常的PCSK9信号传导和胆固醇代谢。功能获得性突变会导致持续性高胆固醇血症和不良健康后果，而功能丧失性突变通常会导致低胆固醇血症，并可能作为预防肝脏、心血管系统和中枢神经系统疾病的保护因素。最近的基因组研究试图确定此类突变的终末器官效应，并继续寻找PCSK9在肝外器官系统中发挥更广泛作用的证据。尽管如此，我们对PCSK9及其调节以及它对肝脏以外疾病风险的影响的理解仍存在很大差距。本综述整合了来自广泛科学学科和实验范式的数据，旨在描述PCSK9在中枢神经系统中与脑部疾病和神经精神疾病相关的作用，并探讨PCSK9抑制剂和PCSK9基因遗传变异对疾病结局（包括神经和神经精神疾病）的临床潜力。
