AlphaB-crystallin modified by methylglyoxal prevents fibrillization of α-synuclein A53T

AlphaB-crystallin is a small heat shock protein that is found in the eye lens, retina, heart, brain, skin, and skeletal muscle. Mutations of αB-crystallin lead to the development of cataracts, human muscle and heart disorders. The role of non-enzymatic glycation of αB-crystallin in the development of pathological processes has been little studied. The aim of this study was to evaluate the influence of enhanced methylglyoxal (MGO) level on the functions of αB-crystallin. We modified recombinant αB-crystallin (aB-Cr) by MGO and investigated the effect of this modification on different functions of aB-Cr: ability to suppress protein thermo-aggregation, promote protein refolding, and suppress the amyloid-like aggregation of α-synuclein A53T (αSynA53T, a mutation associated with early-onset Parkinson's disease). It was shown that MGO modifies 8 Arg residues per αB-Cr subunit yielding methylglyoxal-derived hydroimidazolone (MG-H) and results in cross-links between the protein subunits. The modification reduces the ability of αB-Cr to suppress thermo-aggregation of catalase and to promote refolding glyceraldehyde-3-phosphate dehydrogenase. At the same time, modification by MGO enhances the ability of αB-Cr to suppress fibrillization of αSynA53T: while the addition of native αB-Cr results in shorter fibrils, MGO-modified αB-Cr completely prevents fibrillization of αSynA53T, yielding amorphous aggregates that are less toxic to the cells compared to αSynA53T fibrils. Therefore, the effect of MGO on various αB-crystallin functions may be different, resulting in a decrease or increase in its activity.