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Eric S. Green, Michael D. Menz, Matthew M. LaVail, John G. Flannery; Characterization of Rhodopsin Mis-sorting and Constitutive Activation in a Transgenic Rat Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2000;41(6):1546-1553.
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purpose. To determine the extent to which rhodopsin mis-sorting and constitutive
activation of the phototransduction cascade contribute to retinal
degeneration in a transgenic rat model of retinitis pigmentosa.
methods. Retinas from transgenic rats expressing truncated rhodopsin
(Ser334ter) were examined by light and electron microscopic
immunocytochemistry at several time points. Retinal degeneration in
transgenic rats raised in darkness was evaluated by quantification of
outer nuclear layer thickness and by electroretinography.
results. Mutant rhodopsin was found at inappropriately high levels in the plasma
membrane and cytoplasm of Ser334ter rat photoreceptors. When the cell
death rate was high this mis-sorting was severe, but mis-sorting
attenuated greatly at later stages of degeneration, as the cell death
rate decreased. The distributions of two other outer segment proteins
(the cGMP-gated channel and peripherin) were examined and found to be
sorted normally within the photoreceptors of these rats. Raising
Ser334ter transgenic rats in darkness resulted in minimal rescue from
conclusions. Because dark rearing Ser334ter rats results in little rescue, it is
concluded that constitutive activation of the phototransduction cascade
does not contribute significantly to photoreceptor cell death in this
rat model. The nature of the rhodopsin sorting defect and the
correlation between the severity of mis-sorting and rate of cell death
indicate that truncated rhodopsin may cause apoptosis by interfering
with normal cellular machinery in the post-Golgi transport pathway or
in the plasma membrane.
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