Crystallin-Derived Mini-Chaperones as Protein Aggregation Inhibitors

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DESCRIPTION (provided by applicant): A large number of diverse diseases, including cataract, some types of glaucoma, Alzheimer disease, diabetes and cancer to name only a few, are now known to share the common feature of aggregated, misfolded or modified protein deposits. The pathological hallmark in this group of diseases is protein aggregation and deposition in specific cells, tissues or organs. The pathological similarities indicate that common principles that govern protein interactions underlie protein misfolding degenerative diseases. Therefore, a therapeutic modality developed for one conformational disease might also be applicable to another conformational disease when the protein folding/aggregation problem is the same in each disease. Lens crystallin aggregation and cataractogenesis is a classic example of a protein misfolding and aggregation disease. Over time, the cumulative effects of crystallin aggregation in the lens results in age-related cataract formation. In certain forms of glaucoma, the protein myocilin misfolds and aggregates in the trabecular meshwork, interfering with the outflow of aqueous humor and causing elevated intraocular pressure. The goal of this project is to develop therapeutic molecules that exert inhibitory actions on protein misfolding and aggregation. Our in vitro studies have shown that the addition of a-crystallin to aggregating proteins stops a further increase in aggregation and light scattering of denaturing/unfolding proteins. We have also found that specific sequences in a-crystallin subunits have the capacity to suppress aggregation of denaturing proteins. However, the full potential of a-crystallin-derived peptides (mini-chaperones) is yet to be realized. We propose to develop 1-crystallin-derived peptides and test their function as active mini-chaperones capable of suppressing crystallin and myocilin protein aggregation. The Specific Aims are the following: Specific Aim 1. a) Design and synthesize peptide modulator(s) of protein-protein interactions based on the aA-crystallin-derived mini-chaperone sequence. b) Characterize the in vivo activity of the newly identified mini-chaperone(s) using cell culture-based assay methods. Specific Aim 2: Investigate the potential of mini-aA-crystallin chaperone for suppressing aggregation of glaucoma-causing mutant myocilin. Successful development of peptide-based therapeutics for protein aggregation diseases will offer new therapeutic approaches. These innovative studies will give us new insights into potential interventions for protein misfolding diseases, not only of the eye but also of other parts of the body. This effort would expand the therapeutic strategies for wide range of protein misfolding diseases. PUBLIC HEALTH RELEVANCE: Cataract and glaucoma, along with a host of other diseases, result from abnormal interaction of proteins in the cells. The goals of this research are to develop and test lens protein 1-crystallin-derived peptides as active mini-chaperones capable of suppressing protein aggregation.