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

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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.