title: Increased O-GlcNAc causes disrupted lens fiber cell differentiation and cataracts.
abstract: Diminished proteolytic functionality in the lens may cause cataracts. We have reported that O-GlcNAc is an endogenous inhibitor of the proteasome. We hypothesize that in the lens there is a cause-and-effect relationship between proteasome inhibition by O-GlcNAc, and cataract formation. To demonstrate this, we established novel transgenic mouse models to over-express a dominant-negative form of O-GlcNAcase, GK-NCOAT, in the lens. Expression of GK-NCOAT suppresses removal of O-GlcNAc from proteins, resulting in increased levels of O-GlcNAc in the lenses of our transgenic mice, along with decreased proteasome function. We observed that transgenic mice developed markedly larger cataracts than controls and lens fiber cell denucleation was inhibited. Our study suggests that increased O-GlcNAc in the lens could lead to cataract formation and attenuation of lens fiber cell denucleation by inhibition of proteasome function. These findings may explain why cataract formation is a common complication of diabetes since O-GlcNAc is derived from glucose.
authors: Department of Medicine, Division of Endocrinology, Diabetes and metabolism, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294, USA.
authors: Kai
authors: K
authors: Wang
authors: Shiuh-Rong
authors: SR
authors: Ho
authors: Weiming
authors: W
authors: Mao
authors: Ping
authors: P
authors: Huang
authors: Fengxue
authors: F
authors: Zhang
authors: Erik M
authors: EM
authors: Schwiebert
authors: Jeffrey E
authors: JE
authors: Kudlow
authors: Andrew J
authors: AJ
authors: Paterson
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002386:Cataract / Q000473:pathology*; D002454:Cell Differentiation; D051548:Histone Acetyltransferases / Q000235:genetics; D006821:Hyaluronoglucosaminidase / Q000235:genetics; D007908:Lens, Crystalline / Q000166:cytology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D038222:gamma-Crystallins / Q000378:metabolism*
chemical_list: D038222:gamma-Crystallins; D051548:Histone Acetyltransferases; D006821:Hyaluronoglucosaminidase; D000117:Acetylglucosamine