Exploring the Roles of Manganese in Neurons

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ABSTRACT Manganese (Mn) is an essential yet underappreciated nutrient required for proper growth and development. Mn is necessary for mitochondrial generation of reactive oxygen species, which is important for cell survival. Although Mn plays a broad role in the human body, the brain appears to be the most sensitive organ to Mn dysregulation. Recent epidemiological surveys have found that both low and high Mn levels are associated with cognitive and behavioral impairment in children. Moreover, exposure to high levels of Mn can lead to brain Mn accumulation and a parkinsonian-like disorder. Thus, the correlation between Mn dysregulation and brain malfunction in humans is well established. However, the causal relationship between the two remains to be determined. Do abnormal Mn levels result in impaired cognitive development? Why is brain development so sensitive to dysregulation of Mn? The lack of experimental approaches that can manipulate Mn levels in only the brain has been the major roadblock to addressing these important questions. The overarching goal of my research group is to contribute to the understanding of how Mn regulation underlies normal and pathological brain development and functions. My research group and others recently discovered a role for solute carrier family 39, member 8 (SLC39A8) in Mn homeostasis that is linked to neurodevelopment. SLC39A8 is a transmembrane metal-ion transporter that is known to transport various metals such as zinc, iron, cadmium, selenium, and Mn. In 2015, mutations in SLC39A8 were reported in neurodevelopmental disorders (NDDs) characterized by intellectual disabilities and brain atrophy. Notably, patients with SLC39A8 mutations exhibited severely low levels of Mn in the blood, but other metal levels in these patients were normal. My research group demonstrated that the disease-associated mutations abrogated Mn uptake activity and impaired mitochondrial functions. In these studies, the major perturbations in Mn levels contrast strikingly with minor alterations in other metal levels, confirming that SLC39A8 is essential for Mn homeostasis and that Mn is a main substrate that requires SLC39A8 in vivo. At present, how SLC39A8 deficiency contributes NDDs remains unknown. The objective of this project is to establish a mouse model that we can use to explore the roles of Mn in neurons. We have generated Slc39a8 neuron-specific-knockout (Slc39a8-NSKO) mice, in which Slc39a8 is deleted specifically in neurons. We will test whether Slc39a8-NSKO mice are an animal model of neuronal Mn deficiency. The proposed project is exploratory because control of Mn levels specifically within neurons lacks precedent; therefore, the project fits well with the R21 mechanism. Completion of these aims will likely provide the first mouse model to explore the roles of Mn in neurons. As such, this research will open an avenue to the study of Mn homeostasis in the brain and a better understanding of the etiology underlying Mn-related NDDs, which could lead to novel approaches for developing therapeutic strategies.