Development of MESH1 inhibitors to treat ferroptosis-associated neurodegeneration

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All living organisms encounter a wide variety of metabolic and environmental stress and have developed various stress-response mechanisms that promote survival. In bacteria, the main stress-response mechanism is the “stringent response” which is triggered by the accumulation of the alarmone (p)ppGpp. It orchestrates extensive transcriptional changes to promote stress survival. Metazoan genomes encode a homolog of bacterial SpoT—MESH1—that can hydrolyze ppGpp in vitro and functionally complements SpoT in E. coli. However, neither a homolog of the (p)ppGpp synthetase nor (p)ppGpp itself has been found in metazoans, mystifying the function and relevant substrate(s) of MESH1 in mammalian cells. Recently, our research has revealed that MESH1 is the first cytosolic NADPH phosphatase that is essential for ferroptosis. Ferroptosis is a newly- recognized form of cell death which is characterized by iron dependency and lipid peroxidation. The induction of MESH1 under ferroptosis contributes to NADPH and GSH depletion. Therefore, genetic removal of MESH1 robustly protects cells from ferroptosis. As ferroptosis is involved in neuronal cell death in neurodegenerative diseases, such as Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD), we hypothesize that inhibition of ferroptosis by small molecule MESH1 inhibitors may protect neurons from ferroptosis in AD/ADRD. To test our hypothesis, we assemble an integrative scientific team with complementary expertise and propose the following two specific aims: First, we will develop and optimize small molecule MESH1 inhibitors derived from the top two validated hit compounds. Next, we will determine the activity and specificity of MESH1 inhibitors to block ferroptosis in cultured cells and in organotypic brain slice culture models of AD/ADRD. Collectively, the successful execution of the proposal will identify novel chemical inhibitors of MESH1 and ferroptosis to improve treatment outcomes for patients with age-related AD/ADRD.