Marian Kies Memorial Award for 1999
Dr. Donald C. Shields
Dr. Donald C. Shields
Donald Sheilds, an MD/PhD student with Naren Banik at the Medical University of South Carolina, was the recipient of the 1999 Marian Kies Award for his studies on calpain activation in autoimmune demyelinating diseases. In autoimmune demyelinating diseases such as experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS), myelin membrane structure is destabilized as myelin proteins are lost. Calcium activated neutral proteinase (calpain) has been implicated in myelinolysis since this endopeptidase degrades all major myelin proteins and is localized in glial/inflammatory cells involved in demyelination. To investigate the role of calpain in EAE, Dr. Sheilds evaluated calpain activity and expression in the spleens, spinal cords, and optic nerves of Lewis rats with acute EAE. He found that in both the optic nerve and spinal cords of these animals, calpain activity and translational expression were significantly increased during the peak stage of disease (days 10-12 post-induction) in comparison to rats injected only with complete Freund’s adjuvant (CFA). However, at the transcriptional level, no significant alterations in calpain expression were observed by RT-PCR. Using double immunofluorescent labeling, calpain was commonly observed in astrocytes from CFA controls. In animals with EAE, calpain expression was markedly increased in activated microglia, reactive astrocytes, activated T cells, and activated macrophages. In the spleen, calpain activity and translational expression were significantly upregulated by day 4 post-induction (in both CFA controls and animals with EAE) in activated macrophages and activated T cells in comparison to normal controls. Again, no significant changes in calpain transcriptional expression were observed. To compare the previous findings in EAE with that of MS, human brain samples from normal controls, neurological controls (Parkinson’s and Alzheimer’s diseases), and MS lesions were obtained and similarly evaluated. Calpain activity and translational expression were markedly increased in the normal appearing white matter and demyelinating lesions of patients with MS compared to normal and neurological controls. As in EAE, activated glial/inflammatory cells were responsible for these increases with no observed changes in calpain transcriptional expression. These studies suggest calpain expression is upregulated post-transcriptionally in glial and infiltrating inflammatory cells upon activation. Since calpain is known to participate in apoptosis, T cell migration, and myelin protein degradation the above findings suggest that calpain may play a critical role in demyelination prior to and during acute stages of autoimmune demyelinating diseases.
SL 11/15/2007