Biological And Biochemical Characterization Of Sigma Receptors

Sigma 受体的生物学和生化特征

• 批准号: 10699645
• 负责人: Tsung-Ping Ping Su
• 金额: $ 151.2万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699645
• 关键词: Adrenal Glands; Affect; Agonist; Alzheimer' s Disease; Amnesia; Animal Disease Models; Animal Genetics; Anxiety; Autophagocytosis; Behavioral Symptoms; Biochemical; Biological; Brain; C9ORF72; Cell Death; Cell Nucleus; Cell physiology; Cells; Clinical; Cocaine; Cocaine Dependence; Cytosol; Degenerative Disorder; Disease; Endoplasmic Reticulum; Foundations; Functional disorder; Goals; Heart; Homeostasis; Huntington Disease; Impairment; In Vitro; Inherited; Integral Membrane Protein; Laboratories; Life; Ligands; Liver; Lung; Malignant Neoplasms; Membrane; Memory impairment; Mental Depression; Methamphetamine; Mitochondria; Mitochondrial Diseases; Molecular; Molecular Chaperones; Molecular Mechanisms of Action; Mus; Mutation; National Institute of Drug Abuse; Nuclear; Nuclear Pore; Nuclear Pore Complex Proteins; Organ; Pain; Parkinsonian Disorders; Pathology; Patients; Peripheral; Pharmacology; Phase II/III Clinical Trial; Play; Pore Proteins; Property; Proteins; RNA; Respiration; Role; Spleen; Stroke; WFS1 gene; Wolfram Syndrome; Zebrafish; craving; frontotemporal lobar dementia-amyotrophic lateral sclerosis; human disease; mitochondrial dysfunction; non-opioid analgesic; novel; novel therapeutic intervention; novel therapeutics; nucleocytoplasmic transport; overexpression; preclinical study; receptor; recruit; sigma receptors; sigma-1 receptor; therapeutic development; transcription factor

Since my laboratory at the NIDA IRP identified the sigma-1 receptor in 1982, many preclinical studies have shown that sigma-1 receptors and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimer disease, pain, and cocaine addiction. In this fiscal year from Oct 1/2021-Sept 30/2022, we discovered two mechanisms of action of the sigma-1 receptor: (A) The sigma-1 receptor plays a critical role in a survival mechanism called autophagy; and (B) The sigma-1 receptor is pivotal in a clinically unmet disease called the Wolfram's Syndrome. Findings are explained as follows. (A) Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importin1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired. (B) The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences and currently no treatment is available. Therefore, the aim of this study was to identify and propose a novel relevant therapy. The pathology is related to the deficient activity of wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed mitochondria associated-ER membranes (MAMs). Inherited mutations usually reduce the proteins stability, altering its homeostasis and ultimately reducing ER to mitochondria Ca2+ transfer resulting in mitochondrial dysfunction and cell death. We here demonstrate that activation of the sigma-1 receptor (S1R), an endoplasmic reticulum resident protein involved in Ca2+ transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored Ca2+ transfer and mitochondrial respiration in vitro and was able to alleviate the behavioral symptoms observed in the genetic animal models of the disease, i.e. hyperlocomotion in Wfs1abKO zebrafish and memory deficits and anxiety in Wfs1Exon8 mice. Our findings provide a new therapeutic strategy for Wolfram syndrome patients, by efficiently boosting MAM function using the ligand operated S1R chaperone. Moreover, such strategy could be expanded to other degenerative and mitochondrial diseases involving MAMs dysfunction.

自从我在NIDA IRP的实验室于1982年发现了sigma-1受体以来，许多临床前研究表明sigma-1受体和相关配体与中风、健忘症、抑郁症、癌症、阿尔茨海默病、疼痛和可卡因成瘾有关。 在2021年10月1日至2022年9月30日的本财政年度，我们发现了sigma-1受体的两种作用机制：（A）sigma-1受体在称为自噬的生存机制中起着关键作用;（B）sigma-1受体在称为Wolfram综合征的临床未满足疾病中起着关键作用。 调查结果解释如下。 (A)自噬是细胞生存的重要过程，与许多疾病有关。自噬中的关键步骤是转录因子TFEB通过KPNB 1/importin 1通过核孔（NP）从细胞质转运到细胞核中。在肌萎缩性侧索硬化-额颞叶变性（ALS-FTD）的C9 orf 72亚型中，六核苷酸（G4 C2）RNA扩增（HRE）破坏了TFEB的核质转运，损害了自噬。在这里，我们表明分子伴侣，SIGMAR 1/Sigma-1受体（Sigma非阿片样物质细胞内受体1），通过陪伴NP蛋白（即，核孔蛋白）POM 121，其募集KPNB 1。在NSC 34细胞中，HRE通过干扰SIGMAR 1和POM 121之间的关联来减少TFEB转运，导致TFEB、KPNB 1和自噬标志物LC 3-II的核水平降低。SIGMAR 1或POM 121的过表达，或用高度选择性和有效的SIGMAR 1激动剂普利多匹定治疗，目前在ALS和亨廷顿病的2/3期临床试验中，挽救了所有这些缺陷。我们的结果表明核孔蛋白POM 121不仅是一种结构核孔蛋白，而且还表明SIGMAR 1激动剂（例如普多比啶）可用于治疗自噬受损的疾病。 (B)Wolfram综合征是一种罕见的常染色体隐性遗传疾病，影响许多器官，具有危及生命的后果，目前没有治疗方法。因此，本研究的目的是确定并提出一种新的相关治疗方法。病理学与钨蛋白活性不足有关，钨蛋白是一种内质网（ER）跨膜蛋白，参与ER和线粒体之间的接触，称为线粒体相关ER膜（MAMs）。遗传突变通常降低蛋白质的稳定性，改变其稳态，并最终减少ER向线粒体Ca 2+的转移，导致线粒体功能障碍和细胞死亡。我们在这里表明，激活的σ-1受体（S1 R），内质网驻留蛋白参与钙离子转运，可以抵消由于钨蛋白缺乏MAMs的功能改变。S1 R激动剂PRE-084在体外恢复了Ca 2+转移和线粒体呼吸，并能够减轻在该疾病的遗传动物模型中观察到的行为症状，即Wfs 1abKO斑马鱼的过度运动和Wfs 1 Exon 8小鼠的记忆缺陷和焦虑。我们的发现为Wolfram综合征患者提供了一种新的治疗策略，通过使用配体操作的S1 R伴侣有效地增强MAM功能。此外，这种策略可以扩展到其他退行性和线粒体疾病涉及MAMs功能障碍。