This administrative supplement is submitted in response to Notice Number: NOT-AG-18-039: Alzheimer's- focused administrative supplements for NIH grants that are not focused on Alzheimer's disease (AD). This supplement outlines experiments to extend the parent R01, A novel role of fascin in cancer metastasis (1R01CA233844-01) to determine the impact of fascin inhibition and disruption of mitochondrial actin filaments on neuronal oxidative stress and neural degeneration such as AD. Although fascin has been mostly studied in the context of cancer metastasis, there are reports indicating reduced fascin expression levels and increased fascin oxidation in AD patient brain when compared to non-demented control. Fascin knockout mice also have enlarged lateral ventricle and smaller brain, indicating loss of neural cells and potential neurodegeneration. In the parent R01 we proposed to study a novel mitochondrial role of fascin in cancer metastasis. Our data support a hypothesis where fascin promotes lung cancer metastasis by augmenting mitochondrial OXPHOS. Fascin inhibitor is currently in phase I clinical trial as anti-metastasis agents. However, the potential side effects of fascin inhibitors in the brain is unclear. Since the mitochondrial dysfunction is known to be crucial for AD pathogenesis and progression, we hypothesize that inhibition of mitochondrial OXPHOS in neuronal cells by fascin inhibitor might exacerbate AD initiation and progression. In this supplement we will study the mitochondrial role of fascin in ?-amyloid peptide neurotoxicity and oxidative stress resistance using primary neuron and genetically engineered mouse model recently developed in our lab. We will further evaluate the neurotoxicity of fascin inhibitors. The success of proposed experiments in this supplement will be crucial to understand the mitochondrial role of fascin in neurodegenerative disease such AD, and will contribute to the development of anti-metastasis fascin inhibitors with minimal side effects on neuronal cell function and neurodegeneration.
PUBLIC HEALTH RELEVENCE: This supplement investigates the role of fascin in neuronal cell survival, neurodegeneration and the effects of fascin inhibitors on Alzheimer?s disease pathogenesis. The findings from this supplement application will potentially shed new light on the role of the actin cytoskeleton in neuronal metabolism, and allow the design of better anti-metastasis therapies with minimal side effects.
