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.

肌萎缩性外侧硬化症（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。这些神经从大脑和脊髓带有信号到肌肉，以进行运动和呼吸。这些患者的运动神经的丧失导致进行性肌肉麻痹，并最终由于呼吸问题而死亡。约有约10％的ALS病例具有家族史，其在具有不同功能的几种基因中鉴定出突变。然而，驱动ALS中驱动运动神经元丧失的分子机制仍然鲜为人知。理解这些机制对于开发可以停止甚至扭转无情神经元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，可以将患者的皮肤或血细胞转化为胚胎状态。这些重编程的细胞称为诱导多能干细胞（IPSC），并有可能转化为体内任何细胞类型。因此，现在可以将来自ALS患者的IPSC诱使成为运动神经元，即ALS患者丢失的相同细胞。这项技术使菜肴中ALS模型的发展开发，使科学家能够询问这些细胞中出了什么问题会导致它们在ALS中死亡。使用这样的型号，我发现了一个称为WNT的重要信号通路可能是造成细胞内的MN死亡的原因，类似于智能手机上的特定应用程序。每个途径旨在执行特定任务。信号通路可以与其他途径进行通信，以在单元格内执行复杂功能。途径活动的不当增加或减少会对细胞造成严重的后果。这样的途径是Wnt信号通路。该途径在人体中的大多数细胞（包括神经系统）中起作用。在神经系统中，它调节重要功能，例如神经元的结构以及神经元如何相互交流。鉴于其重要的WNT信号受到严格调节。我实验室中产生的数据表明，在ALS患者的运动神经中，该途径异常激活。此外，我们发现，如果使用药物抑制此途径，ALS运动神经在菜肴中的寿命更长。但是，我们不了解该途径的激活如何导致运动神经死亡，以及抑制该途径是否会对运动神经产生其他意想不到的后果。该建议将使用IPSC技术从ALS患者中产生运动神经，并使用这些神经来了解Wnt在ALS中的功能的细节。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，并强调是否可以将Wnt作为ALS治疗。

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