The molecular chaperone properties of α-crystallin are believed to play a key role in maintaining the transparency of the lens.
28 Thus, the prevalent hypothesis for age-related cataracts is that, with time, other lenticular proteins will unfold and/or become modified and start to unfold, overwhelming the chaperone capacity of α-crystallin and causing protein aggregates to form.
3,29,30 In the present study, the levels of α-crystallins were decreased (2-D DIGE) in all ARNC nuclei, compared with those in age-matched normal controls, and the decreased level of αA-crystallin became more obvious as the cataracts progressed from grade II to grade IV (
Fig. 3). The result that αA-crystallin was the most abundant protein in the HMW aggregates suggests the possibility of cross-linking between αA-crystallin and other proteins. The band of HMW aggregates was not seen in the normal lens nuclei (
Fig. 4A), indicating that little aggregation occurred or that the aggregation was reversible in deaggregating reagents. These observations were confirmed by Western blot analyses of αA-crystallin (
Figs. 6A and
6B). In Wistar rats, the loss of αA-crystallin is observed in the aging lens (10, 16, 30, 90, 180, and 360 days), and selenite-induced cataract rat models lose more αA-crystallin compared with age-matched normal rats.
31 This phenomenon may be similar in human lenses. In vitro, α-crystallins can protect β- and γ-crystallins and other proteins against denaturation and subsequent aggregation.
3,32 The mechanism of this protection involves preferential binding of the partially denatured protein to a central region of an α-crystallin complex,
33 and the substrate proteins of the α-crystallins are in a molten globule state.
34,35 The α-crystallins may perform a similar function in vivo, binding to and protecting other crystallins against further denaturation.
28