Neurobiological Basis of Neuronal Survival

内质网（ER）和线粒体之间的界面，称为线粒体相关ER膜（MAM），在将Ca 2+从ER供应到线粒体中以产生用于细胞存活的能量化合物ATP中起重要作用。我们在这里报告说，在MAM的sigma-1受体在临床上未满足的疾病称为Wolfram综合征中起着关键作用。调查结果总结如下。 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。

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.