Prion-induced photoreceptor degeneration begins with misfolded prion protein accumulation in cones at two distinct sites: cilia and ribbon synapses

Abstract

Accumulation of misfolded host proteins is central to neuropathogenesis of numerous human brain diseases including prion and prion-like diseases. Neurons of retina are also affected by these diseases. Previously, our group and others found that prion-induced retinal damage to photoreceptor cells in mice and humans resembled pathology of human retinitis pigmentosa caused by mutations in retinal proteins. Here, using confocal, epifluorescent and electron microscopy we followed deposition of disease-associated prion protein (PrPSc) and its association with damage to critical retinal structures following intracerebral prion inoculation. The earliest time and place of retinal PrPSc deposition was 67 days post-inoculation (dpi) on the inner segment (IS) of cone photoreceptors. At 104 and 118 dpi, PrPSc was associated with the base of cilia and swollen cone inner segments, suggesting ciliopathy as a pathogenic mechanism. By 118 dpi, PrPSc was deposited in both rods and cones which showed rootlet damage in the IS, and photoreceptor cell death was indicated by thinning of the outer nuclear layer. In the outer plexiform layer (OPL) in uninfected mice, normal host PrP (PrPC) was mainly associated with cone bipolar cell processes, but in infected mice, at 118 dpi, PrPSc was detected on cone and rod bipolar cell dendrites extending into ribbon synapses. Loss of ribbon synapses in cone pedicles and rod spherules in the OPL was observed to precede destruction of most rods and cones over the next 2–3 weeks. However, bipolar cells and horizontal cells were less damaged, indicating high selectivity among neurons for injury by prions. PrPSc deposition in cone and rod inner segments and on the bipolar cell processes participating in ribbon synapses appear to be critical early events leading to damage and death of photoreceptors after prion infection. These mechanisms may also occur in human retinitis pigmentosa and prion-like diseases, such as AD.

Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

“…The results described above warrant further investigation on the accumulation of aggregated protein in the photoreceptors, especially since it appears as one of the events leading to photoreceptor death, as suggested by our RNA-Seq analyses and also by another group (51).…”

Minimal change prion retinopathy: Morphometric comparison of retinal and brain prion deposits in Creutzfeldt-Jakob disease

“…Our findings confirm prior reports of retinal PrP Sc deposition in sCJD cases ( Head et al, 2003 , 2005 ; Orru et al, 2018 ; Takao et al, 2018 ) as well as in mouse models ( Striebel et al, 2021 ). As with these studies, we find the strongest PrP Sc deposition in the OPL where discrete ovoid deposits of PrP Sc result in a “beads-on-a-string” appearance along the horizontal length of the lamina.…”

“…Although further ultrastructural investigations of the structures involved in the OPL PrP Sc deposits are warranted, we hypothesize that PrP Sc is accumulating at the synaptic ribbon where the presynaptic terminals of rod and cone photoreceptors from the ONL connect with the postsynaptic dendrites of bipolar and amacrine interneurons from the INL. Evidence of this PrP localization has recently been reported by Striebel et al (2021) , who identified PrP Sc accumulation in ribbon synapses and cilia of photoreceptors in mouse models of prion disease. The presence of PrP Sc deposits at retinal synaptic junctions could alter or disrupt this retinal circuitry, result in photoreceptor degeneration, and perhaps contribute to visual symptoms reported in sCJD.…”

Transcriptomic analysis identifies novel potential biomarkers and highlights cilium-related biological processes in the early stages of prion disease in mice

“…In addition, a previous study has reported that prion-induced photoreceptor degeneration begins with PrP Sc accumulation in cones at two distinct sites including cilia and ribbon synapses. This result indicated the association of cilium-related biological processes with prion disease in the retina [ 31 ]. Although there was no validation at the RNA level for the differentially expressed genes found in this study, since several pieces of evidence have indicated the association of cilium with prion diseases, further investigation of cilium in prion diseases at the protein level is highly desirable in the future.…”