The long term goal of this research project is to understand iron regulation in the nervous system. Many neuropathological conditions are thought to involve disruptions in iron metabolism including Parkinson's and Alzheimer's disease, but relatively little knowledge exists concerning iron metabolism in the brain. This proposal focuses on the three major proteins in iron metabolism; transferrin (Tf; iron mobilization), the transferrin receptor, and ferritin (iron storage). Recently, Tf, and the mRNA for Tf, iron and ferritin have all been demonstrated either specifically or predominantly in oligodendrocytes. The long established function of oligodendrocytes as myelin producing cells actually only accounts for the function of 1/3 of their population. Perivascular and perineuronal oligodendrocytes exist in gray matter (which contain the major iron components) whose function under normal conditions is not established. These gray matter and a subset of white matter oligodendrocytes may be iron regulatory cells. The independence of the expression of the three major iron proteins and iron accumulation to myelination will be demonstrated using a chronic)quaking) and a reversible (female carrier of the jimpy gene) hypomyelinating murine mutants. The levels of iron proteins should reach a plateau in both the animal models, but will undergo a second increase in the reversible hypomyelinating model in association with increased metabolis demands of myelination. Immunohistochemistry, quantitative assay, receptor binding and molecular approaches will be used; the latter technique will yield information regarding whether control of iron protein synthesis is at the transcriptional or translational leve. Tissue culture studies will determine if iron and Tf in culture medium effect the synthesis of ferritin, the Tf receptor and Tf by normal and """"""""jimpy"""""""" oligodendrocytes. Also the mechanism of iron uptake by oligodendrocytes will be determined. Finally, we will compare accumulation of iron components in Schwann cells in tissue culture under myelinating and non-myelinating conditions. The significance of this proposal is that it addresses two area of neurobiology about which little is known: iron regulation in the nervous system and oligodendrocytic/Schwann cell physiology and is thus relevant to neurodegenerative disorders and dysmyelinating diseases.
