Hyunglok Chung

My ultimate career goal is to elucidate the function of Very long-chain fatty acids (VLCFA, ?22 carbons in length) during development and how they contribute to neuroinflammation and disease. Lipids are critical for neuronal development, synaptic plasticity, and function. Abnormal lipid metabolism contributes to the pathogenesis of several diseases associated with glial dysfunction, such as Alzheimer's disease and Parkinson's disease. Using a genetic model system and collaboration with clinicians, I discovered variants in ACOX1 (Acyl-CoA Oxidase1) in a patient with ataxia, progressive motor loss, and myeloneuropathy. Loss-of-function mutations in Drosophila ACOX1 lead to VLCFA accumulation, reduced lifespan, impaired synaptic transmission, and glial and axonal loss, while gain-of-function causes increased levels of ACOX1 protein and function, resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. These findings indicate conserved functions of ACOX1, provide compelling evidence that variants in ACOX1 cause glial loss, and establish proof of principle that we can study the pathogenesis of disease with this humanized fly system. Using functional analysis in Drosophila, I discovered the mechanisms underlying ACOX1 deficiency and gain and identified therapeutic avenues for both loss and gain in patients (Chung et al., 2020). My recent data show that glia and immune cells with elevated levels of VLCFA may act synergistically to cause a neuroinflammatory response and that this may serve as a model for Multiple Sclerosis (MS). Therefore, I aim to study VLCFA in glia and immune cells to elucidate the molecular underpinnings of neuroinflammatory diseases.