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S. L. Hose, C. Zhang, R. Grebe, G. A. Lutty, J. S. Zigler, Jr., D. Sinha; βA3/a1-Crystallin is Required for Cellular Integrity of Astrocytes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4035.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effect of the Nuc1 mutation in βA3/A1-crystallin on astrocytes.
The Nuc1 spontaneous mutant rat (Molecular & Cellular Neuroscience, 2008) and age-matched Sprague-Dawley wildtype rats were used in these studies. Astrocytes were cultured from brains of Wildtype and Nuc1 neonatal rats. Expression of autophagy proteins in the astrocytes was assessed by immunohistochemistry and western blotting. Structural changes in the astrocytes including the assembly of intermediate filaments were evaluated using electron microscopy.
In the retina and the brain, βA3/A1-crystallin is expressed only in astrocytes. Our studies with the Nuc1 mutant astrocytes indicate that βA3/A1-crystallin plays an important role in the assembly of intermediate filaments (Ifs) in that large aggregates of Ifs are observed in the cytoplasm. The mutation also causes nuclear membrane fragility, change in nuclear shape and altered disposition of chromatin. In Nuc1 astrocytes, the nucleolus is larger, singular and consistently located at the periphery of the nucleus rather than in the more central location typical of normal astrocytes. In addition, unique perinuclear vacuolar structures containing amorphous and electron-dense material are present in the mutant astrocytes. These structures appear to be part of an autophagy process. The activation of autophagy is supported by an increase in Beclin 1 in Nuc1 astrocytes compared to normal during postnatal development. Beclin 1 is required for initiation of autophagosome formation during autophagy.
Our studies with Nuc1 suggest that βA3/A1-crystallin may have an important role in maintaining the cellular integrity of astrocytes. Our studies also indicate that autophagy, the only known process in eukaryotic cells for degrading cellular organelles and recycling them to ensure cell survival, is severely affected in astrocytes with the βA3/A1-crystallin gene mutation, Nuc1.
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