Investigating the Role of the Mitochondrial Calcium Uniporter in Inflammatory Neurodegeneration

The Mitochondrial Calcium Uniporter (MCU) regulates Ca2+-influx into mitochondria. In case of neurological disease, an excessive Ca2+ influx (Caoverload) plays a major role in post-lesional neuronal degeneration and death. Materials and Methods: To further elucidate the role of the MCU in CNS pathophysiology, we generated neuron-specific MCU knockout mice in order to study them in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). We hypothesize that neuronal damage can be reduced by inactivatingthe MCU, offering therapeutic opportunities. We crossbred neuron-specific cre (NexCre) transgenic and homozygous loxP floxed mice. After one generation we obtained hemizygous, neuron-specific Cre (NexCre) mice which were heterozygous for the floxed MCUgene. These animals were crossbred with homozygous, loxP floxed MCU gene mice to obtain an F2 generation with a homozygous knockout for MCU in Nexexpressing cells (neurons). Results: Genotyping confirmed the successful breeding of such homozygous floxed animals with Cre expression. The transgenic mice are healthy and do not show any conspicuous differences as compared to their non-transgeniclittermates. Conclusion: We will use these mice, induce EAE and compare the disease courses of knockout mice with non-transgenic controls. Furthermore, we will analyze Ca2+-dependent mechanisms of neuronal degeneration by use of histopathological and live imaging techniques.