The aim of this project will be to test the feasibility of developing and testing a novel peptide inhibitor that will specifically block Par4 interaction with the atypical protein kinase C isoform zeta. Par4 is a protein well established as a mediator of neuronal degeneration associated with the C pathogenesis of Alzheimer's disease. Clear evidence exists demonstrating that apoptotic stimuli cause Par4 to bind zetaPKC followed by cell death. Moreover, elevated Par4 suppresses the activity of the transcription factor nuclear factor kappa B, whose activity is required for transcription of prosurvival genes. The binding domain, which mediates the interaction between Par4 and zetaPKC has been mapped to the leucine zipper (LZ) domain (amino acids 265-332) of Par4. Moreover, deletion of Par4's LZ inhibits Par4's ability to induce apoptosis. Thus, the specific aims for this exploratory proposal will be: 1) to employ """"""""peptide walking"""""""" to identify a specific peptide within the leucine zipper domain of Par4 that can be used to effectively disrupt interaction of zetaPKC with Par4; 2) to establish uptake of the peptide by cells in culture and delivery of the peptide to brain in vivo; 3) to establish functional inhibition of Par4 activity by the peptide inhibitor, and last; 4) to test the ability of the peptide to block neuronal cell death and restore normal function. Collectively these findings will lead to a significant breakthrough in the development of a designer therapeutic agent, which will protect neurons from the effects of Alzheimer's and other neurodegenerative diseases.
| Du, Yifeng; Wooten, Michael C; Gearing, Marla et al. (2009) Age-associated oxidative damage to the p62 promoter: implications for Alzheimer disease. Free Radic Biol Med 46:492-501 |
