Molecular chaperone function and motor neuron degeneration

为了协调运动，信号必须通过被称为运动神经元的特殊神经细胞从大脑发送到肌肉。其中一些运动神经元非常大，可以在几英尺内发送信号，这使得它们的生物学非常具有挑战性，这意味着它们很容易受到压力和疾病的影响。当这些运动神经元死亡时，就会导致瘫痪。在一些家庭中，由于基因变化，这种瘫痪可以遗传。最近，人们发现一种叫做HSJ1的应激反应蛋白的遗传变化会通过运动神经元的死亡导致瘫痪。我们已经研究这种蛋白质很多年了，知道它可以保护神经细胞，包括运动神经元，免受压力。为了正常运作，所有细胞都需要平衡新蛋白质的产生和清除，这在蛋白质受损的压力时期尤为重要。因此，进化已经发展出一个称为分子伴侣的蛋白质家族来帮助维持这种平衡，HSJ1是神经细胞中重要的分子伴侣。为了研究HSJ1在神经细胞中的功能，并理解为什么它对运动神经元如此重要，我们现在已经对遗传性瘫痪患者的细胞进行了重新编程，并将用它们来研究人类运动神经元。我们还开发了一种模拟人类疾病的动物模型。在这个项目中，我们将使用这些模型来发现瘫痪患者的分子基础。在这种疾病中导致瘫痪的事件很可能也会影响运动神经元在其他疾病中的功能，因此我们认为这将告诉我们更多关于其他类型的运动神经元疾病和神经细胞死亡的信息。我们还将利用这种详细的分子理解来开发新的治疗方法，可能用于这种类型的瘫痪和潜在的其他形式的神经细胞死亡，如运动神经元疾病、帕金森病和阿尔茨海默病。

In order to co-ordinate movement, signals must be sent from the brain to the muscles along specialized nerve cells called motor neurons. Some of these motor neurons are very large and send signals over several feet, this makes their biology very challenging and means that they can be susceptible to stress and disease. When these motor neurons die it leads to paralysis. In some families this paralysis can be inherited because of genetic changes. Recently, it was discovered that inherited changes in a stress response protein called HSJ1 lead to paralysis through the death of motor neurons. We have been studying this protein for many years and know that it can protect nerve cells, including motor neurons, from stress. To function normally all cells need to balance their production of new proteins with their removal and this is especially important at times of stress, when proteins can get damaged. Therefore, evolution has developed a family of proteins called molecular chaperones to help maintain this balance and HSJ1 is an important molecular chaperone in nerve cells. To investigate how HSJ1 functions in nerve cells and understand why it is so critical to motor neurons, we have now reprogrammed cells from patients with inherited paralysis and will use them to study human motor neurons. We also have developed an animal model that mimics the human disease. In this project we will use these models to discover the molecular basis for paralysis in patients. It is likely that the events that cause paralysis in this disease will also affect how motor neurons function in other diseases and therefore we think this will tell us more about other types of motor neuron disease and nerve cell death in general. We will also use this detailed molecular understanding to develop new treatments that might be used for this type of paralysis and potentially other forms of nerve cell death such as motor neuron disease, Parkinson's and Alzheimer's disease.