Abstract
Retinitis Pigmentosa (RP) begins with the death of rod photoreceptors and is slowly followed by a gradual loss of cones and a rearrangement of the remaining retinal neurons. Clusterin is a chaperone protein that protects cells and is involved in various pathophysiological stresses, including retinal degeneration. Using a well-established transgenic rat model of RP (rhodopsin S334ter), we investigated the effects of clusterin on rod photoreceptor survival. To investigate the role of clusterin in S334ter-line3 retinas, Voronoi analysis and immunohistochemistry were used to evaluate the geometry of rod distribution. Additionally, immunoblot analysis, Bax activation, STAT3 and Akt phosphorylation were used to evaluate the pathway involved in rod cell protection. In this study, clusterin (10μg/ml) intravitreal treatment produced robust preservation of rod photoreceptors in S334ter-line3 retina. The mean number of rods in 1mm2 was significantly greater in clusterin injected RP retinas (postnatal (P) 30, P45, P60, & P75) than in age-matched saline injected RP retinas (P<0.01). Clusterin activated Akt, STAT3 and significantly reduced Bax activity; in addition to inducing phosphorylated STAT3 in Müller cells, which suggests it may indirectly acts on photoreceptors. Thus, clusterin treatment may interferes with mechanisms leading to rod death by suppressing cell death through activation of Akt and STAT3, followed by Bax suppression. Novel insights into the pathway of how clusterin promotes the rod cell survival suggest this treatment may be a potential therapeutic strategy to slow progression of vision loss in human RP.
Highlights
Retinitis Pigmentosa (RP) is the cause of inherited blindness that results from gene mutations [1,2,3,4,5,6]
The intensity of the clusterin precursor-immunoreactive band was stronger in RP retinas than in normal retinas
We investigated if an exogenous application of clusterin could affect the rod survival in RP retina, with the hypothesis that clusterin was an “innate defender.”
Summary
Retinitis Pigmentosa (RP) is the cause of inherited blindness that results from gene mutations [1,2,3,4,5,6]. Regardless of the underlying genetic defect, the disease begins with the degeneration of rods followed by the degeneration of cones. This event eventually leads to a rewiring of the inner-retinal neurons [3, 4, 7,8,9,10,11,12]. In the RP rhodopsin S334ter-line retina, rods die in” hot spots” or clusters [21]. These clusters of rod death appear to be embedded in a background of random cell death in the P14-P17 whole-mount retinas. Some rod holes are visible until P45, and by P60, surviving rods are scattered in the whole-mount in the S334ter retina[22]
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