The in vitro Toxicity of Photoreceptors by the Human Prion Protein Fragment P106–126 Correlates to the Retinal PrP Distribution

Abstract

Abstract: : Purpose:Retinal lesions including photoreceptor damages have been reported in transmissible spongiform encephalopathies (TSE). To further understand the retinal physiopathology of the TSE, we examined the PrP^c subcellular distribution in the rat and human retina. This cellular distribution was subsequently correlated to the toxicity of synthetic prion peptide (PrP106–126) in retinal cell culture.Methods:The subcellular distribution of PrP^c was investigated by immunocytochemistry with confocal microscopy in the rat and human retina. The toxicity of the 106–126 peptide was investigated on adult pig mixed retinal cell culture incubated for 4 days. Results:PrP^c was present in the OPL as punctuated appearances in both the rat and human retina. It colocalized with arrestin in the photoreceptor terminals, but did not colocalize with cone photoreceptor terminals identified by PNA. In addition, PrP^c immunolabelled structures were often seen in close apposition with PKC–α immunopositive rod bipolar cell dendrite tips and calbindin or paravalbumin–immunopositive horizontal cell dendrite tips. Thus, PrP^c appeared specifically localized in rod spherules. The treatment of mixed retinal cells with PrP106–126 resulted in a significant decrease in the number of rods, but not a decrease in the cones and ganglion cells. Rod cell death was confirmed by TUNEL staining of rhodopsin–positive cells while microglial cells identified by the ILB–4 specific marker appeared to have proliferated in the presence of PrP106–126. Conclusions:These observations indicate that the Prion protein PrP^c is specifically localized in rods but not cone photoreceptors rendering them sensitive to the toxicity of the PrP106–126 peptide. These data could explain the visual impairment described in TSE diseases.

Keywords: photoreceptors • apoptosis/cell death • pathology: human