Calcineurin activation causes retinal ganglion cell degeneration.
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 articleSubject
AnimalsAxons
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
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Show full item recordScholars@Duke
Roland Albert Matsouaka
Assistant Professor of Biostatistics & Bioinformatics

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