title: CRYβA3/A1-Crystallin Knockout Develops Nuclear Cataract and Causes Impaired Lysosomal Cargo Clearance and Calpain Activation.
abstract: βA3/A1-crystallin is an abundant structural protein of the lens that is very critical for lens function. Many different genetic mutations have been shown to associate with different types of cataracts in humans and in animal models. βA3/A1-crystallin has four Greek key-motifs that organize into two crystallin domains. It shown to bind calcium with moderate affinity and has putative calcium-binding site. Other than in the lens, βA3/A1 is also expressed in retinal astrocytes, retinal pigment epithelial (RPE) cells, and retinal ganglion cells. The function of βA3/A1-crystallin in the retinal cell types is well studied; however, a clear understanding of the function of this protein in the lens has not yet been established. In the current study, we generated the βA3/A1-crystallin knockout (KO) mouse and explored the function of βA3/A1-crystallin in lens development. Our results showed that βA3-KO mice develop congenital nuclear cataract and exhibit persistent fetal vasculature condition. At the cellular level KO lenses show defective lysosomal clearance and accumulation of nuclei, mitochondria, and autophagic cargo in the outer cortical region of the lens. In addition, the calcium level and the expression and activity of calpain-3 were increased in KO lenses. Taken together, these results suggest the lack of βA3-crystallin function in lenses, alters calcium homeostasis which in turn causes lysosomal defects and calpain activation. These defects are responsible for the development of nuclear cataract in KO lenses.
authors: Department of Vision Sciences, School of Optometry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Shylaja
authors: S
authors: Hegde
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Robert A
authors: RA
authors: Kesterson
authors: Department of Vision Sciences, School of Optometry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Om P
authors: OP
authors: Srivastava
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003459:Crystallins / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006706:Homeostasis; D007150:Immunohistochemistry; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008853:Microscopy; D008928:Mitochondria / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D038205:beta-Crystallin A Chain
chemical_list: C051374:Cryba1 protein, mouse; D003459:Crystallins; D012333:RNA, Messenger; D038205:beta-Crystallin A Chain; D002154:Calpain; C112682:Capn1 protein, mouse; D002118:Calcium