Bioenergetic deficit in neurodegeneration: studies in motor neuron disease (MND) (2016-2019)

MND is a fatal neurodegenerative disease for which there is no effective treatment. In Australia there are around 1900 people living with MND at any given time. The socioeconomic burden of MND is estimated to be a considerable A$52,000/patient. In the absence of a cure for MND, more research is needed to find new therapeutic approaches. Studies indicate that patients with MND have impairments in whole body physiology and energy homeostasis, with evidence that an imbalance in energy metabolism negatively influences the rate of progression of disease. Our preliminary and published data led us to hypothesise that a vicious cycle of bioenergetic deficit underpins disease pathogenesis in MND. This innovative project will be the first to investigate and modulate energy metabolism responses to neurodegeneration in a mouse model of MND, and in human iPSC-derived neurons and myoblast-derived muscle fibres to define thow energetic deficit causes the catastrophic and relentless death of motor neurons and progressive muscle weakness in MND. Our multidisciplinary approach, and the use of therapeutic compounds that target multiple facets of the disease are crucial for treating the multifactorial nature of MND. Demonstration of a neuroprotective role of diazoxide-targeted improvements to systemic and cellular bioenergetics will be of clinical significance. The FDA approved status of diazoxide and the array of highly-selective and potent diazoxide analogs will facilitate the expediting of clinical trials to assess the safety, tolerability, and efficacy of these compounds in MND. More broadly, the outcomes of this project will provide insights that extend beyond the need to understand the fundamental mechanisms that trigger the onset and progression of MND. Insights gained from our work will guide future approaches aimed at targeting metabolic pathways or accommodating for energy deficit as promising therapeutic strategies for MND, and neurodegenerat...