Altered Chaperone-like Activity of α-Crystallins Promotes Cataractogenesis

Despite the enormous number of studies demonstrating changes in the chaperone-like activity of alpha-crystallins in vitro, little is known about how these changes influence life-long lens transparency in vivo. Using the gamma B-crystallin I4F mutant protein as a target for alpha A-crystallins, we examined how cataract phenotypes are modulated by interactions between alpha-crystallins with altered chaperone-like activities and gamma B-I4F proteins in vivo. Double heterozygous alpha-crystallin knock-out alpha A(+/-) alpha B(+/-) mice with a decreased amount of alpha-crystallins were used to simulate reduced total alpha-crystallin chaperone-like activity in vivo. We found that triple heterozygous alpha A(+/-) alpha B(+/-) gamma B(I4F/+) mice developed more severe whole cataracts than heterozygous gamma B(I4F/+) mice. Thus, total chaperone-like activity of alpha-crystallins is important for maintaining lens transparency. We further tested whether mutant alpha A-crystallin Y118D proteins with increased chaperone-like activity influenced the whole cataract caused by the gamma B-I4F mutation. Unexpectedly, compound alpha A(Y118D/+) gamma B(I4F/+) mutant lenses displayed severe nuclear cataracts, whereas the lens cortex remained unaffected. Thus, the synergistic effect of alpha A-Y118D and gamma B-I4F mutant proteins is detrimental to the transparency only in the lens core. alpha-Crystallins with different chaperone-like activities are likely required in the lens cortex and nucleus for maintaining transparency.