Investigator: Marla Tipping, Providence College
Theme: Neuroscience
Title: Metabolic dysregulation in Frontotemporal Dementia
Award: SURF PUI Training Award (2022-2024)

Abstract: A common attribute of neurodegenerative disease is a change in the way cells break down and utilize nutrients, as well as their ability to build new macromolecules. Collectively, this is referred to as metabolic reprogramming, and in each disease the specific manner in which these changes occur are varied. The neurodegenerative disease Frontotemporal dementia (FTD) is diagnosed by a characteristic decrease in glucose uptake in neurons of the frontotemporal region of the brain and an individual patient’s results is suggestive of how the disease will manifest. Frontotemporal dementia (FTD) is the second most common form of dementia in patients under 65 years of age. This disease is typically fatal within six to eight years from diagnosis and there are currently no treatment options. It is generally characterized by a progressive decline in behavior, personality and judgement, while memory is typically intact until end stages. Clinical and basic research suggests that metabolic processes are dysregulated in FTD and contribute to disease pathogenesis. Recent literature has shown that changes in metabolism can be targeted for therapeutic treatment in other neurodegenerative diseases. For example, in Amyotrophic Lateral Sclerosis (ALS) increasing cellular glucose levels have been shown to have protective properties for motor function and increased survival time in mammalian models. This suggests that metabolism may be a promising process to exploit for delay of FTD disease progression. The proposed project will investigate metabolic dysregulation in Drosophila modeling FTD by the over expression of dipeptides resulting from a C9ORF72 repeat expansion. Metabolic pathways will be interrogated by addition of chemical stressors and subsequent measuring of oxygen consumption and extracellular acidification in brains harboring these dipeptides. Impaired pathways will be further analyzed by studying changes in the gene expression of key metabolic enzymes within the pathway, as well signaling pathways that regulate these processes. Metabolic profiling will also be utilized to gain a broader understanding of the metabolic dysregulation. The results of these proposed experiments will elucidate potential targets for therapeutic treatment and suggest insight into the mechanism behind these metabolic changes.

Relevance: Neurodegenerative diseases, such as Frontotemporal Dementia (FTD), are often diagnosed by metabolic dysfunction of neurons. However, few studies investigate the metabolic changes that occur and whether these can be exploited to delay progression of these fatal diseases. This project aims to identify the metabolic pathways that are altered in FTD and determine the cause of this dysregulation with the goal of providing targets for potential treatment options.