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

WNT 信号失调是肌萎缩侧索硬化症运动神经元丢失的驱动因素

基本信息

批准号：
MR/T033029/1
负责人：
Akshay Bhinge
金额：
$ 61.6万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT033029%2F1
关键词：
Dysregulated WNT signaling driver motor

项目摘要

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.

肌萎缩侧索硬化症 (ALS)（也称为运动神经元疾病）是由运动神经或神经元丧失引起的。这些神经将信号从大脑和脊髓传递到肌肉以进行运动和呼吸。这些患者运动神经的丧失会导致进行性肌肉麻痹，最终因呼吸问题而死亡。大约 10% 的 ALS 病例有家族史，在多个具有不同功能的基因中发现了突变。然而，人们对 ALS 运动神经元损失的分子机制仍知之甚少。了解这些机制对于开发能够阻止甚至逆转神经元持续损失的疗法至关重要。随着一种称为重编程的新干细胞技术的出现，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），有可能转化为体内的任何细胞类型。因此，来自 ALS 患者的 iPSC 现在可以被诱导成为运动神经元，即与 ALS 患者丢失的同类细胞。这项技术能够在培养皿中开发 ALS 人类模型，使科学家能够探究这些细胞内的问题导致它们死于 ALS。通过这些模型，我发现一种名为 WNT 的重要信号通路可能是导致 ALS 中 MN 死亡的原因。细胞内的信号通路与智能手机上的特定应用程序类似。每个途径都旨在执行特定任务。信号通路可以与其他通路通信以执行细胞内的复杂功能。通路活性的不当增加或减少可能会给细胞带来严重后果。 WNT信号通路就是这样的通路之一。该途径在人体的大多数细胞中发挥作用，包括神经系统。在神经系统内，它调节重要的功能，例如神经元的结构以及神经元如何相互通信。鉴于其重要性，WNT 信号传导受到严格监管。我的实验室生成的数据表明，ALS 患者的运动神经中的这条通路被异常激活。此外，我们发现，如果使用药物抑制该通路，ALS 运动神经在培养皿中的寿命会更长。然而，我们不知道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。该提案将利用 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。这项研究的结果将更深入地了解 ALS 运动神经死亡的原因，并强调 WNT 是否可以作为 ALS 的靶向治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.

DOI：
10.1186/s13041-021-00810-w
发表时间：
2021-06-26
期刊：
Molecular brain
影响因子：
3.6
作者：
Steg LC;Shireby GL;Imm J;Davies JP;Franklin A;Flynn R;Namboori SC;Bhinge A;Jeffries AR;Burrage J;Neilson GWA;Walker EM;Perfect LW;Price J;McAlonan G;Srivastava DP;Bray NJ;Cope EL;Jones KM;Allen ND;Pishva E;Dempster EL;Lunnon K;Mill J;Hannon E
通讯作者：
Hannon E

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

新型肌萎缩侧索硬化症人类模型中内源性 TDP43 的快速诱导错误定位