Targeting mitochondria to develop next-generation therapies for the childhood motor neuron disease, spinal muscular atrophy

Motor neuron diseases (MND) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are currently incurable diseases of the nervous system that carry a significant physical, emotional, and societal burden for patients and their families. The annual incidence of SMA is 1:6,000–1:10,000 live births, while ALS has a life-time risk of 1:300. At present, there is no cure for either disease. Moreover, although clinical trials for SMA have shown success, there are limitations to widespread use of these current therapies, whereas no successful therapies have been identified for ALS. Thus, efforts to identify new therapies that can treat or manage the disease are essential. Motor neurons are the key nerve cells that connect the brain and spinal cord to the muscles of the body. Given that degeneration and loss of lower motor neurons (those that originate in the spinal cord) is a common feature of MND, the ability to slow or halt degeneration of these motor neurons offers a potentially powerful new therapeutic approach. Previous work has shown that some motor neurons possess an inherent ‘natural’ protective capacity that allows them to resist degeneration during MND. Through a series of preliminary experiments, we now know that one major difference between ‘vulnerable’ and ‘disease-resistant’ motor neurons is their ability to generate and handle energy. This is due to differences in levels of genes and proteins contributing to ‘bioenergetic’ pathways (those involved in utilising energy for biological reactions), which are largely located in mitochondria: the “power-house” of each and every cell of the body. Animal models are engineered to mimic human diseases, and as such, are a useful research tool. In this proposal, I will use a combination of zebrafish and mouse models of SMA and ALS to test the hypothesis that targeting bioenergetic pathways is a viable therapeutic strategy for protecting motor neurons from degeneration in MND. Accordingly, this project aims to identify specific energy-related genes that can be therapeutically targeted to protect motor neurons against MND. This will significantly enhance our understanding of the cellular and molecular mechanisms underlying motor neuron degeneration in MND. To facilitate rapid transition from pre-clinical research to clinical trials in patients with MND, drugs that have been previously approved for use in humans for other medical conditions will purposefully be incorporated.