Mitochondria and metabolism in neurodegeneration

总结

SUMMARY Currently, ~5.8 million Americans suffer from Alzheimer's disease (AD)1 and there remain no approved therapeutics to lessen the associated neuronal dysfunction and cell death. Various AD clinical trials targeting the “amyloid cascade” have proven unsuccessful, suggesting a dire need to rethink AD disease progression. Alterations in cellular calcium (iCa2+) and mitochondrial function are reported as critical molecular contributors to AD pathogenesis. Our lab has previously shown that genetic modulation of either mCa2+ uptake or efflux is a powerful way to limit mitochondrial dysfunction and cell death in the context of cell stress featuring elevated iCa2+. As causal evidence of impaired mCa2+ exchange in AD, we generated multiple mutant mouse models to modulate neuronal NCLX expression, the primary mechanism for 2+ efflux in excitable cells, and mCa discovered that impaired mitochondrial calcium efflux proceeds neuropathology and memory decline in 3xTg- AD mouse model. In addition to alterations in mCa 2+ efflux, we also discovered significant proteomic remodeling of the mitochondrial calcium uniporter channel (mtCU). The mtCU is required for acute Ca2+ uptake into the mitochondrial matrix where it regulates mitochondrial function. The mtCU is a multiprotein channel, consisting of pore-forming, scaffold, and regulatory components. To date, there are no published in vivo studies using genetic models to define the contribution of mCa2+ uptake with AD disease progression and given our published findings regarding the role of mCa2+ efflux in AD pathogenesis17, it's imperative that we mechanistically define the mCa2+ uptake pathway prior to proceeding with therapeutic development. In this project, we hypothesize that mCa2+overload is a primary contributor to AD pathology by promoting metabolic dysfunction and neuronal cell death, and that reducing mtCU-dependent mCa2+ uptake will impede neurodegeneration and AD pathogenesis. Further, using complex mutant mouse models we will systematically define the mitochondrial metabolomic and proteomic changes associated with AD progression and alterations in mCa2+ flux. Optimally, these studies will identify new therapeutic targets for the treatment of AD.