IS THERE A ROLE FOR ENDOPLASMIC RETICULUM STRESS IN THE PATHOGENESIS OF ALS?

运动神经元病（MND）是一种破坏性强且进展迅速的成人发病疾病；大多数患者在诊断后2-5年死亡。MND的特点是神经系统中被称为“运动神经元”的特定细胞死亡。不幸的是，MND目前病因不明，也没有有效的治疗方法。本研究旨在探讨MND运动神经元退化的机制。一些形式的MND是遗传的，与一种叫做SOD1的蛋白质的突变有关，但突变是如何导致细胞死亡的尚不清楚。然而，已知SOD1突变体会大量聚集在一起，这与毒性有关。在之前的研究中，我们发现正常情况下，SOD1是由细胞分泌的，它可以保护运动神经元免受氧化损伤。然而，SOD1突变体不像正常蛋白那样分泌，使细胞容易受到损伤。此外，由于SOD1突变体的分泌功能障碍，负责分泌的细胞室内质网（ER）也处于应激状态。我们的数据表明，内质网应激导致“细胞自杀”途径的激活，导致运动神经元的死亡。然而，对于内质网中的分子事件如何导致MND中的细胞死亡，我们知之甚少。本建议将详细研究这些过程。在其他研究中，我们发现一种名为“PDI”的分子抑制突变SOD1的聚集，并且在我们的MND实验室模型中大量产生。由于PDI能够保护细胞免受SOD1聚集的毒性作用，这一提议将确定PDI是否可能成为MND的新治疗靶点。我们的发现既新颖又令人兴奋，并提出了以前未被探索的疾病机制和新的治疗靶点。一旦我们了解了运动神经元发生的基本机制，我们就可以设计出特定的治疗方法来阻止疾病的发展，延长人类精神病患者的生命。

Motor neuron disease (MND) is a devastating and rapidly progressing adult onset disease; most patients die 2-5 years after diagnosis. MND is characterized by the death of specific cells, called 'motor neurons' within the nervous system. Unfortunatley, MND currently has an unknown cause and no effective treatment. This proposal aims to study the mechanisms that trigger degeneration of motor neurons in MND. Some forms of MND are inherited and linked to mutations in a protein called SOD1, but how the mutations lead to cell death is unclear. However, SOD1 mutants are known to clump together in large aggregates and this is linked to toxicity. In a previous study, we found that normally SOD1 is secreted from the cell where it can protect the motor neuron from oxidative damage. However SOD1 mutants are not secreted as well as the normal protein, leaving the cell vulnerable to damage. In addition, the compartment of the cell responsible for secretion,the 'endoplasmic reticulum' (ER), is under stress due to secretory dysfunction of mutant SOD1. Our data suggest that this ER stress leads to the activation of 'cell suicide' pathways, leading to death of the motor neuron. However, very little is known about how molecular events in the ER lead to cell death in MND. This proposal will examine these processes in detail. In other studies, we found that a molecule called 'PDI' inhibits mutant SOD1 from aggregation and is made in large quantities in our laboratory models of MND. This proposal will determine if PDI is potentially a new therapeutic target for MND due its ability to protect the cell from the toxic effects of SOD1 aggregation. Our findings are both novel and exciting and propose previously unexplored mechanisms of disease and new theraputic targets. Once we understand the basic mechanisms occuring in the motor neuron, which we can design specific therapies to halt the progression of the disease and prolong the life of human MND patients.