Abstract
BackgroundAlpha crystallin is an oligomer composed of two types of subunits, alpha-A and alpha-B crystallin, and is the major constituent of human lens. The temperature induced condensation of alpha-crystallin, the main cause for eye lens opacification (cataract), is a two step-process, a nucleation followed by an aggregation phase, and a protective effect towards the aggregation is exhibited over the alpha crystallin phase transition temperature (Tc = 318.16 K).Methods/ResultsTo investigate if a modulation of the subunit interactions over Tc could trigger the protective mechanism towards the aggregation, we followed, by using simultaneously static and dynamic light scattering, the temperature induced condensation of alpha-crystallin. By developing a mathematical model able to uncouple the nucleation and aggregation processes, we find a previously unobserved transition in the nucleation rate constant. Its temperature dependence allows to determine fundamental structural parameters, the chemical potential (Δμ) and the interfacial tension (γ) of the aggregating phase, that characterize subunit interactions.Conclusions/General SignificanceThe decrease of both Δμ and γ at Tc, and a relative increase in solubility, reveal a significative decrease in the strenght of alpha-crystallin subunits interactions, which protects from supramolecolar condensation in hypertermic conditions. On the whole, we suggest a general approach able to understand the structural and kinetic mechanisms involved in aggregation-related diseases and in drugs development and testing.
Highlights
Cataract is the most common cause of blindness, and, of enormous medical and economical relevance worldwide
The second exponential growth is instead consistent with an reaction limited cluster-cluster aggregation theory (RLCA) process where high molecular weight forms of alpha-crystallin (HMW) after a large number of collisions can stick together [19],[35]
And below Tc the aggregations are well characterized in the framework of RLCA theory: the final morphology of the aggregates is similar, the aggregation kinetics seem completely different [18]
Summary
Cataract is the most common cause of blindness, and, of enormous medical and economical relevance worldwide. The social impact and economic cost of cataract have motivated extensive research on the lens and an enormous amount of knowledge has been accumulated [1]. Pathological studies of cataractous lenses have revealed that cataracts are composed of protein aggregates that precipitate in eye lens cells. The prevalent proteins within the eye lens are the crystallins. Alpha crystallin is an oligomer composed of two types of subunits, alpha-A and alpha-B crystallin, and is the major constituent of human lens. The temperature induced condensation of alpha-crystallin, the main cause for eye lens opacification (cataract), is a two step-process, a nucleation followed by an aggregation phase, and a protective effect towards the aggregation is exhibited over the alpha crystallin phase transition temperature (Tc = 318.16 K)
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