ABNORMAL PROTEINS IN HUMAN AND ANIMAL LENSES

Alpha neoproteins are molecules built of A and B subunits as alpha crystallin but have a different quaternary structure than the native protein. The formation of such abnormal lens proteins has been proven first in our laboratory experimentally. Alpha neoproteins are formed: a) when the ratio of isolated monomeric A-chains to monomeric B-chains in a mixture is lower than 2:1 (1); b) when B-chains are added to alpha crystallin in solution (2); and c) as a result of modification of A- chains built into alpha crystallin (3). This proposal stems from our recent finding that alpha neoprotein molecules are formed in nature. They occur in normal and cataractous lenses of experimental animals and humans and their content increases with age (4). The aim of these investigations is to analyze potential differences among alpha neoproteins formed in normal lenses of different age, and in cataractous lenses of humans and animals, and study potential mechanisms leading to alpha neoprotein formation. We shall concentrate on the structural variation of alpha neoproteins and their A and B chains dependent on: age, cataract inducing agents and duration of cataract. The proposed research will involve: 1) Analysis of the heterogeneity of various alpha neoproteins; 2) Comparison of the A- and B-chain ratio of alpha neoproteins in normal lenses from animals of different ages and in lenses with cataracts; 3) Determination of the number and quantity of different A and B chains in various alpha neoproteins; 4) Comparison of antigenic determinants formed by the quaternary structure of various alpha neoproteins; 5) Comparison of antigenic determinants of A- and B-chains of various alpha neoproteins; 6) Determination of the reactivity of SH groups in various alpha neoproteins; 7) Investigation of possible mechanisms of alpha neoprotein formation; 8) Investigation of the relative role of changes in the rate of A and B biosynthesis as well as the role of chain modification in the formation of alpha neoproteins. The clinical approach of this research proposal is to investigate the possible role of neoproteins in animal and human lens-induced uveitis. We expect that the investigations of the mechanisms of lens abnormal protein formation should expand our knowledge on aging and cataract in the lens.