| The studies in this thesis were designed to investigate the consequences of iron deficiency in the central nervous system. Two different models of iron-deficient states were used for our investigation. Restless Legs Syndrome (RLS) was studied with a focus on iron misregulation. RLS is characterized by an irresistible desire to move the extremities, with the legs generally affected to a greater degree than the arms. We measured the levels of whole-molecule ferritin, H-ferritin, L-ferritin, and transferrin in the cerebrospinal fluid from patients with RLS, with the goal of attaining a profile of these proteins in the central nervous system. We also determined that the iron-signaling hormone hepcidin is present in the CSF, and that its levels are altered in RLS. To investigate the type of brain iron misregulation possibly occurring in RLS and its potential causes, we studied the short- and long-term consequences of early iron deficiency on rat brain. We utilized microarray analysis of the whole brain homogenate of the developmental iron deficient rat model. The rats were born to iron deficient mothers, and were analyzed at two different ages: at 21 days, while weaning and iron deficient; and at six months, after a recovery period consisting of normal iron intake for five months. Over 300 genes were significantly changed in the 21-day animals. Several significant gene clusters of interest were identified, including: myelin-related, signal transduction, channel/pore class transporter and alpha-type channel activity, ion channel activity, DNA binding, transitional metal binding, and solute carrier family members. The impact of the misregulation of the genes in these clusters can cause decreased myelination and conductivity, as well as impaired cell-to-cell and intracellular signaling, in addition to the expected changes in iron-related genes. In the six month formerly iron-deficient animals, only twelve genes were identified as significantly changed, reflecting considerably fewer changes than the acute iron-deficient state, but changes that are long-term. Of the twelve genes found, all were down-regulated, and seven were either estimated sequence tags or transcribed sequences, leaving five genes whose function can be discussed. Of the five genes, two are cytoplasmic, two are nuclear, and one is found in both the nucleus and cytoplasm. The downregulation of genes from the six month animals represents weakened cytoskeletal stability and infrastructure of neurons, decreased nucleic acid translation, and decreased responsiveness to oxidative stress. (Abstract shortened by UMI.)... |
