The Toxicity of the PrP106-126 Prion Peptide on Cultured Photoreceptors Correlates with the Prion Protein Distribution in the Mammalian and Human Retina

Abstract

In patients affected by Creutzfeldt-Jakob disease and in animals affected by transmissible spongiform encephalopathies, retinal functions are altered, and major spongiform changes are observed in the outer plexiform layer where photoreceptors have their synaptic terminals. In the present study, the prion protein PrP c was found to form aggregates in rod photoreceptor terminals from both rat and human retina, whereas no labeling was observed in cone photoreceptors. Discrete staining was also detected in the inner plexiform layer where the prion protein was located at human amacrine cell synapses. In mixed porcine retinal cell cultures, the PrP106-126 prion peptide triggered a 61% rod photoreceptor cell loss by apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling, whereas cone photoreceptors were not affected. Amacrine cells were also reduced by 47% in contrast to ganglion cells. Although this cell loss was associated with a 5.5-fold increase in microglial cells, the strict correlation between the PrP c prion protein expression and the peptide toxicity suggested that this toxicity did not rely on the release of a toxic compound by glial cells. These results provide new insights Transmissible spongiform encephalopathies in humans and in animals are linked to the transconformation of the prion protein PrP c into a proteinase-resistant form PrP res . 1 These neurological disorders exhibit common pathological symptoms like vacuolization of the neurophils, astrocytosis, and loss of neurons. 2 In patients with CreutzfeldtJakob disease, alteration of the retinal function was attested by the decrease in the electroretinogram b-wave amplitude, 3-5 which reflects the activity of bipolar cells postsynaptic to photoreceptors. These early electroretinogram changes were even proposed as a diagnostic measurement for the disease. 6 In histology, major spongiform changes were observed in the outer plexiform layer (OPL) where photoreceptors have their synaptic terminals, and only moderate changes were observed in the inner plexiform layer (IPL) and ganglion cell layer. 5 These localizations were consistent with the reported accumulation of the pathogenic form of the prion protein, PrP res , throughout the plexiform layers of the human retina. 7 The in vivo retina has been used on many occasions to study the progression of the disease in animal models because of its organized structure, its in vivo access for intraocular injection, and the possibility to correlate the

Long time remodeling during retinal degeneration evaluated by optical coherence tomography, immunocytochemistry and fundus autofluorescence

“…Calbindin, D-28K (CB) Rabbit polyclonal (Oh et al, 2007, Ritchey et al, 2010 Swant (CB-38a) 1:500 Protein kinase C,  isoform (PKC) Rabbit polyclonal (Gong et al, 2007;Barhoum et al, 2008) Santa Cruz Biotechnology was preserved in young animals compared to SD rats; in fact the main value of thickness was higher in young P23H rats than in the older SD normal ones (Panel A vs C). From P19 to 8 months, the total retinal thickness diminished (Panel C, E, G).…”

“…Protein kinase C,  isoform (PKC) Rabbit polyclonal (Gong et al, 2007;Barhoum et al, 2008) Santa Cruz Biotechnology (sc-10800) 1:100…”

EGCG-mediated autophagy flux has a neuroprotection effect via a class III histone deacetylase in primary neuron cells

“…This leads to fibril accumulation and mitochondrial damage, formation of amyloid-like fibrils in vitro , and proteinase K resistance [ 6 , 7 ]. PrP (106-126) expresses significant toxicity to cultured cells, including primary rat hippocampus neuron cells, primary retinal cells, and PC12 cells [ 8 , 9 ]. Furthermore, PrP (106-126) induces the accumulation of cytosolic PrP, which leads to enriched PrP in cell membranes [ 10 ].…”

Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients

“…Although the underlying factors that initiate sCJD are unclear, the cause of prion disease is PrP Sc , an infectious misfolded and aggregated form of the cellular prion protein, PrP C (10,11). PrP C is expressed ubiquitously with the highest levels in neural tissues, including retina, although PrP C expression is higher in brain than retina (12)(13)(14)(15).…”