Dysregulated WNT signaling as a driver of motor neuron loss in Amyotrophic Lateral Sclerosis

肌萎缩性侧索硬化症（ALS）（也称为运动神经元疾病）是由运动神经或神经元的丧失引起的。这些神经将来自大脑和脊髓的信号传递给肌肉，使其运动和呼吸。这些患者的运动神经丧失导致进行性肌肉麻痹，并最终因呼吸问题而死亡。大约10%的ALS患者有几个具有不同功能的基因突变的家族史。然而，在ALS中驱动运动神经元丢失的分子机制仍然知之甚少。了解这些机制对于开发能够阻止甚至逆转这种无情的神经元损失的治疗方法至关重要。随着一种被称为重编程的新干细胞技术的出现，来自患者的皮肤或血细胞可以转化为胚胎状态。这些重新编程的细胞被称为诱导多能干细胞（iPSC），具有转化为体内任何细胞类型的潜力。因此，来自肌萎缩侧索硬化症患者的iPSC现在可以被诱导成运动神经元，也就是肌萎缩侧索硬化症患者丢失的同一种细胞。这项技术可以在培养皿中培育ALS的人体模型，使科学家能够探究这些细胞中出现的问题，从而导致ALS患者死亡。利用这些模型，我发现了一种叫做WNT的重要信号通路可能是导致ALS中MN死亡的原因。细胞内的信号传导途径类似于智能手机上的特定应用程序。每条通路都是为执行特定任务而设计的。在细胞内，信号通路可以与其他通路进行通信，以执行复杂的功能。途径活性的不适当增加或减少可能导致细胞的严重后果。其中一个信号通路是WNT信号通路。这种途径在人体的大多数细胞中起作用，包括神经系统。在神经系统中，它调节着重要的功能，如神经元的结构和神经元如何相互沟通。鉴于其重要性，WNT信号受到严格监管。在我的实验室中产生的数据表明，这条通路在肌萎缩侧索硬化症患者的运动神经中异常激活。此外，我们发现，如果使用药物抑制这一途径，ALS运动神经在培养皿中存活的时间更长。然而，我们不了解该通路的激活如何导致运动神经死亡，以及抑制该通路是否会对运动神经产生其他意想不到的后果。本提案将利用iPSC技术从ALS患者身上生成运动神经，并利用这些神经来了解WNT在ALS中如何发挥作用的细节。这项研究的结果将对ALS运动神经死亡的原因产生更深入的见解，并强调WNT是否可以作为ALS的靶向治疗。

Amyotrophic Lateral Sclerosis (ALS) (also known as motor neuron disease), is caused by a loss of motor nerves or neurons. These nerves carry signals from the brain and spinal cord to the muscles for movement and breathing. Loss of motor nerves in these patients leads to progressive muscle paralysis and eventually death due to breathing problems. About ~10% of ALS cases have a family history with mutations identified in several genes with diverse functions. However, the molecular mechanisms driving motor neuron loss in ALS are still poorly understood. Understanding these mechanisms is paramount in developing therapies that can halt or even reverse the relentless neuronal loss. With the advent of a new stem cell technology called reprogramming, skin or blood cells from patients can be converted into an embryonic state. These reprogrammed cells are called induced pluripotent stem cells (iPSC) and have the potential to be converted to any cell type in the body. Consequently, iPSC's from ALS patients can now be coaxed to become motor neurons i.e. the same kind of cells that are lost in ALS patients. This technology enables the development of human models of ALS in a dish, allowing scientists to interrogate what goes wrong within these cells to cause them to die in ALS. Using such models, I have uncovered that an important signalling pathway called WNT may be responsible for driving MN death in ALS.Signalling pathways within a cell are similar to specific applications on a smart phone. Each pathway is designed to perform a specific task. Signalling pathways can communicate with other pathways to execute complex functions within a cell. Inappropriate increase or decrease in the activity of a pathway can result in serious consequences for a cell. One such pathway is the WNT signalling pathway. This pathway functions in most cells in the human body, including the nervous system. Within the nervous system, it regulates important functions such as the structure of neuron and how neurons communicate with each other. Given its important, WNT signalling is tightly regulated. Data generated in my lab indicates that this pathway is aberrantly activated in motor nerves in ALS patients. Additionally, we found that if this pathway is inhibited using drugs, ALS motor nerves live longer in a dish. However, we do not understand how activation of this pathway causes motor nerves to die and whether inhibiting this pathway will have other unintended consequences on motor nerves. This proposal will use the iPSC technology to generate motor nerves from ALS patients and use these nerves to understand the details of how WNT functions in ALS. The results of this study will generate deeper insights into why ALS motor nerves die and highlight whether WNT can be targeted as a therapy for ALS.