Abstract
Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in lens cells. We have applied synchrotron phase contrast X-ray micro-computed tomography to directly examine an age-related nuclear cataract model in Cx46 knockout (Cx46KO) mice. High-resolution 3D X-ray tomographic images reveal amorphous spots and strip-like dense matter precipitates in lens cores of all examined Cx46KO mice at different ages. The precipitates are predominantly accumulated in the anterior suture regions of lens cores, and they become longer and dense as mice age. Alizarin red staining data confirms the presence of calcium precipitates in lens cores of all Cx46KO mice. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model.
Highlights
Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in lens cells
The lens grows throughout life; equatorial surface epithelial cells differentiate into elongated fiber cells that precisely overlay onto previous generations of fiber cells, and interior fiber cells undergo cell maturation to eliminate intracellular organelles including nucleus, mitochondrion, endoplasmic reticulum and Golgi apparatus for lens transparency[2,3]
All Cx46 knockout (Cx46KO) lenses had electron-dense matters named for precipitates in the lens cores while the 129WT lens was transparent without any precipitates
Summary
Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in lens cells. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model. There are limited studies to directly address the actual components that cause abnormal light scattering of cataracts in live lenses, animals, or human subjects Such knowledge is critical for further understanding the molecular and cellular mechanisms of cataract formation and lens pathology in vivo. Light scattering of severe nuclear cataracts is suggested to be associated with the calpain3-mediated cleavage of crystallin proteins to trigger abnormal protein aggregates
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