Experimental Study Using Multiple Strains of Prion Disease in Cattle Reveals an Inverse Relationship between Incubation Time and Misfolded Prion Accumulation, Neuroinflammation, and Autophagy

Abstract

Proteinopathies result from aberrant folding and accumulation of specific proteins. Currently, there is a lack of knowledge about the factors that influence disease progression, making this a key challenge for the development of therapies for proteinopathies. Because of the similarities between transmissible spongiform encephalopathies (TSEs) and other protein misfolding diseases, TSEs can be used to understand other proteinopathies. Bovine spongiform encephalopathy (BSE) is a TSE that occurs in cattle and can be subdivided into three strains: classic BSE and atypical BSEs (H and L types) that have shorter incubation periods. The NACHT, LRR, and PYD domainsecontaining protein 3 inflammasome is a critical component of the innate immune system that leads to release of IL-1b. Macroautophagy is an intracellular mechanism that plays an essential role in protein clearance. In this study, the retina was used as a model to investigate the relationship between disease incubation period, prion protein accumulation, neuroinflammation, and changes in macroautophagy. We demonstrate that atypical BSEs present with increased prion protein accumulation, neuroinflammation, and decreased autophagy. This work suggests a relationship between disease time course, neuroinflammation, and the autophagic stress response, and may help identify novel therapeutic biomarkers that can delay or prevent the progression of proteinopathies.

An Update on Autophagy in Prion Diseases

“…The differences observed between the two forms of scrapie could reflect differences in the toxicity of both prions, as atypical scrapie displays longer incubation periods than the classical form. In line with these findings, a recent study reported that strain-dependent incubation period is negatively correlated with PrP Sc deposition and neuroinflammation, but positively with autophagy (Mammadova et al, 2020). Retinas from cattle inoculated with classical BSE displayed an upregulation of autophagy indicated by the increase of LC3-II, whereas those inoculated with atypical BSE displayed a downregulation, which suggests that autophagic dysfunction contributes to increased PrP Sc accumulation in atypical BSE, leading to greater neuroinflammation, shorter incubation periods and, therefore, an accelerated disease progression when compared to classical BSE.…”

Differential Accumulation of Misfolded Prion Strains in Natural Hosts of Prion Diseases

“…Relative to other species with prion diseases, cattle with BSE generally have little to no lymphoid distribution of PrP Sc , except for tonsils and transiently in Peyer's patches [50,51]. Though atypical strains appear in older animals, experimental intracranial transmission of atypical strains of BSE results in a much shorter incubation time compared to C-BSE [52,53]. Unlike other species, polymorphisms in the PRNP gene of cattle are extremely rare, thus disease susceptibility and incubation time is not affected by an animal's genotype [53].…”

“…As such, the retina in cases of prion disease is also being studied [100,109]. It has been demonstrated that PrP Sc accumulates in the retina of cattle with BSE [47,52,53,100,[110][111][112], sheep and goats with scrapie [58,109,111,[113][114][115][116][117][118][119][120][121][122][123][124], cervids with CWD [121,[125][126][127][128][129][130][131][132][133], and humans with prion diseases [134][135][136][137].…”

“…The retina is organized into functionally distinct cellular and synaptic layers of cells. PrP Sc differentially accumulates the retinal layers of animals with TSEs depending on factors ranging from strain of TSE to host genotype [52,53,100,119,125,136,139,140]. Once photons of light are transduced by the photoreceptor cells in the outer nuclear layer, the signal is transmitted to the inner nuclear layer and then the ganglion cell layer via the inner and outer plexiform layers.…”

“…Animals with TSEs accumulate PrP Sc in the retina and multiple parts of the visual pathway [109,125,141]. Within the cellular and synaptic layers of the retina, PrP Sc accumulation is most common in the plexiform layers of the retina [115,120,121,126,139,142,143] while the retinal ganglion cells demonstrate a strain-dependent variation of PrP Sc accumulation [52,53,58,100,125].…”