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

James F Striebel,Bruce Chesebro,Jacqueline M Leung,Brent Race,Cindi Schwartz

doi:10.1186/s40478-021-01120-x

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.

Highlights

Prion diseases are progressive neurodegenerative diseases which affect humans as well as numerous wild and domestic animal species
Some people have suspected that prion diseases and prion-like diseases might be susceptible to similar therapeutic interventions [22, 51]
Ethics statement All mice were housed at the Rocky Mountain Laboratories (RML) in an AAALAC-accredited facility in compliance with guidelines provided by the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research Council)

Summary

Introduction

Prion diseases are progressive neurodegenerative diseases which affect humans as well as numerous wild and domestic animal species. These diseases are characterized by vacuolar degeneration of the grey matter and gliosis primarily in grey matter of the CNS. Some people have suspected that prion diseases and prion-like diseases might be susceptible to similar therapeutic interventions [22, 51]. At this time, there is high interest in the mechanisms of pathogenesis of all these diseases

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