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Peter Frederikse, Chinnaswamy Kasinathan, Mahamaya Bhattacharyya, Norman Kleiman; STEP Phosphatase and AMPA Receptor GluA2 Regulation in Diabetes-Induced Cataract in Rabbit. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5945. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Striking similarities between lens fiber cells and neurons suggests these elongated cell types undergo related disease processes. These observations are supported by associations between cataract prevalence and primary neuropsychiatric disorders. Previously, we showed the REST (NRSF) transcription factor network and a network of regulatory mechanisms that govern AMPARs and its pivotal REST-regulated GluA2 subunit also occur in lens, and suggest these fundamental regulatory processes have parallel roles in lens that also may contribute to hallmark calcium increases in cataractogenesis.
The rabbit recapitulates an array of human-like neuronal disease processes we investigated for possible roles in the lens. Adult wt New Zealand white rabbits induced to become diabetic with alloxan maintained blood glucose >350mg/dl. Tissues were taken for in situ immunofluorescence and biochemical studies 15 wks after diabetes onset.
Normal control lenses showed p-Tyr-GluA2 localized at fiber cell membrane spines overlapping with actin and clathrin at these sites, analogous to dendritic spines. In addition to morphological changes typical of diabetic cataract, diseased lenses showed increased STEP61, decreased p-Tyr-GluA2, and loss of p-Tyr-GluA2 at fiber cell spines. These findings are consistent with greater STEP61 in brain in schizophrenia and Alzheimer's disease.
Our results support and extend earlier findings showing lens cells and neurons share global interlocking regulatory networks governing AMPAR/GluA2 expression and function, which also establish the neuronal phenotype and determine neuronal calcium physiology in health and disease. A key finding demonstrating lens p-Tyr-GluA2 localized at fiber cell membrane spines extends basic parallels with dendritic spines. Diabetes-induced increase in lens STEP61with decreased GluA2 Tyr-phosphorylation and loss of p-Tyr-GluA2 from fiber cell spines, parallel changes in neural diseases also linked with diabetes. Increasingly, studies comparing lens cells and neurons surprisingly identify the lens as a faithful in vivo model of neuron biology. Conversely, related disease processes and shared interdependent global regulatory networks in lens and brain highlight a conceptual framework, ported from the nervous system, with testable models of lens calcium regulation, and dysregulation contributing to hallmark calcium increases in cataract.
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