Altered chaperone-like activity of alpha-crystallins promotes cataractogenesis.
Despite the enormous number of studies demonstrating changes in the chaperone-like activity of α-crystallins in vitro, little is known about how these changes influence life-long lens transparency in vivo. Using the γB-crystallin I4F mutant protein as a target for αA-crystallins, we examined how cataract phenotypes are modulated by interactions between α-crystallins with altered chaperone-like activities and γB-I4F proteins in vivo. Double heterozygous α-crystallin knock-out αA(+/-) αB(+/-) mice with a decreased amount of α-crystallins were used to simulate reduced total α-crystallin chaperone-like activity in vivo. We found that triple heterozygous αA(+/-) αB(+/-) γB(I4F/+) mice developed more severe whole cataracts than heterozygous γB(I4F/+) mice. Thus, total chaperone-like activity of α-crystallins is important for maintaining lens transparency. We further tested whether mutant αA-crystallin Y118D proteins with increased chaperone-like activity influenced the whole cataract caused by the γB-I4F mutation. Unexpectedly, compound αA(Y118D/+) γB(I4F/+) mutant lenses displayed severe nuclear cataracts, whereas the lens cortex remained unaffected. Thus, the synergistic effect of αA-Y118D and γB-I4F mutant proteins is detrimental to the transparency only in the lens core. α-Crystallins with different chaperone-like activities are likely required in the lens cortex and nucleus for maintaining transparency.
School of Optometry and Vision Science Program, University of California, Berkeley, California 94720, USA.
Catherine
C
Cheng
Chun-hong
CH
Xia
Qingling
Q
Huang
Linlin
L
Ding
Joseph
J
Horwitz
Xiaohua
X
Gong
D019943:Amino Acid Substitution; D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D006579:Heterozygote; D007904:Lens Cortex, Crystalline / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D038202:alpha-Crystallin A Chain / Q000235:genetics / Q000378:metabolism; D038204:beta-Crystallins / Q000235:genetics / Q000378:metabolism
D038202:alpha-Crystallin A Chain; D038204:beta-Crystallins