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    Calcineurin activation causes retinal ganglion cell degeneration.

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    Date
    2012
    Authors
    Qu, J
    Matsouaka, Roland Albert
    Betensky, RA
    Hyman, BT
    Grosskreutz, CL
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    Abstract
    PURPOSE: We previously reported that calcineurin, a Ca(2+)/calmodulin-dependent serine/threonine phosphatase, is activated and proposed that it participates in retinal ganglion cell (RGC) apoptosis in two rodent ocular hypertension models. In this study, we tested whether calcineurin activation by itself, even in the absence of ocular hypertension, is sufficient to cause RGC degeneration. METHODS: We compared RGC and optic nerve morphology after adeno-associated virus serotype 2 (AAV2)-mediated transduction of RGCs with constitutively active calcineurin (CaNCA) or unactivated, wild-type calcineurin (CaNwt). Retinas and optic nerves were harvested 7-16 weeks after injection of the AAV into mouse vitreous. In flatmounted retinas, the transduced RGCs were identified with immunohistochemistry. The morphology of the RGCs was revealed by immunostaining for neurofilament SMI32 or by using GFP-M transgenic mice. A modified Sholl analysis was applied to analyze the RGC dendritic morphology. Optic nerve damage was assessed with optic nerve grading according to the Morrison standard. RESULTS: CaNwt and CaNCA were highly expressed in the injected eyes. Compared to the CaNwt-expressing RGCs, the CaNCA-expressing RGCs had smaller somas, smaller dendritic field areas, shorter total dendrite lengths, and simpler dendritic branching patterns. At 16 weeks, the CaNCA-expressing eyes had greater optic nerve damage than the CaNwt-expressing eyes. CONCLUSIONS: Calcineurin activation is sufficient to cause RGC dendritic degeneration and optic nerve damage. These data support the hypothesis that calcineurin activation is an important mediator of RGC degeneration, and are consistent with the hypothesis that calcineurin activation may contribute to RGC neurodegeneration in glaucoma.
    Type
    Journal article
    Subject
    Animals
    Axons
    Calcineurin
    Dendrites
    Dependovirus
    Enzyme Activation
    Genetic Vectors
    Green Fluorescent Proteins
    Immunohistochemistry
    Intravitreal Injections
    Mice
    Mice, Transgenic
    Nerve Degeneration
    Optic Nerve
    Retinal Degeneration
    Retinal Ganglion Cells
    Transduction, Genetic
    Transgenes
    Permalink
    https://hdl.handle.net/10161/15726
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    Scholars@Duke

    Matsouaka

    Roland Albert Matsouaka

    Assistant Professor of Biostatistics & Bioinformatics
    Open Access

    Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy

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