Neurobiological Basis of Neuronal Survival

神经元存活的神经生物学基础

• 批准号: 10699654
• 负责人: Tsung-Ping Ping Su
• 金额: $ 100.8万
• 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/10699654
• 关键词: Affect; Agonist; Animal Disease Models; Animal Genetics; Anxiety; Behavioral Symptoms; Brain; Cell Death; Cell Survival; Clinical; Degenerative Disorder; Disease; Endoplasmic Reticulum; Functional disorder; Homeostasis; In Vitro; Inherited; Integral Membrane Protein; Life; Ligands; Membrane; Memory impairment; Metabolism; Mitochondria; Mitochondrial Diseases; Molecular Chaperones; Mus; Mutation; Neurobiology; Neuroglia; Neurons; Organ; Pathologic; Pathology; Patients; Play; Poison; Production; Proteins; Reporting; Respiration; Role; Stress; Therapeutic Agents; WFS1 gene; Wolfram Syndrome; Zebrafish; design; mitochondrial dysfunction; neurobiological mechanism; neuronal survival; novel; novel therapeutic intervention; sigma-1 receptor

The interface between the endoplasmic reticulum (ER) and mitochondria, termed the MAM (Mitochondria-Associated-ER-Membrane), plays an important role in supplying Ca2+ from the ER into mitochondria for the production of energy compound ATP for cellular survival. We report here that the sigma-1 receptor at the MAM plays a critical role in the clinical unmet disease called Wolfram Syndrome. The finding is summarized as follows. 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.

内质网(ER)和线粒体之间的界面被称为线粒体相关膜(MAM)，它在从内质网向线粒体提供钙离子以产生能量化合物ATP以维持细胞生存的过程中发挥着重要作用。我们在此报告MAM上的Sigma-1受体在一种称为Wolfram综合征的临床未得病中起着关键作用。研究结果总结如下。 Wolfram综合征是一种罕见的常染色体隐性遗传病，影响许多器官，会危及生命，目前还没有可用的治疗方法。因此，本研究的目的是确定并提出一种新的相关治疗方法。其病理机制与内质网(ER)跨膜蛋白wolframin活性低下有关，这种跨膜蛋白参与内质网与线粒体之间的接触，称为线粒体相关ER膜(MAMs)。遗传性突变通常会降低蛋白质的稳定性，改变其动态平衡，最终减少内质网到线粒体的钙离子转移，导致线粒体功能障碍和细胞死亡。在这里，我们证明激活Sigma-1受体(S1R)，参与钙离子转运的内质网驻留蛋白，可以抵消由于狼毒蛋白缺乏引起的MAM的功能改变。S1R激动剂Pre-084在体外恢复了钙离子转运和线粒体呼吸，并能够缓解在Wfs1abKO斑马鱼遗传动物模型中观察到的行为症状，即Wfs1abKO斑马鱼的多动和Wfs1Exon8小鼠的记忆障碍和焦虑。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S1R伴侣有效地增强MAM功能。此外，这种策略可以扩展到其他涉及MAMs功能障碍的退行性疾病和线粒体疾病。