Experimental study using multiple strains of prion disease in cattle reveals an inverse relationship between incubation time and misfolded prion accumulation, neuroinflammation, and autophagy

Authors: MAMMADOVA, NAJIBA - Iowa State University; WEST GREENLEE, M - Iowa State University; MOORE, S - Oak Ridge Institute For Science And Education (ORISE); SAKAGUCHI, DONALD - Iowa State University; Greenlee, Justin

Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/20/2020
Publication Date: 7/1/2020
Citation: Mammadova, N., West Greenlee, M.H., Moore, S.J., Sakaguchi, D.S., Greenlee, J.J. 2020. Experimental study using multiple strains of prion disease in cattle reveals an inverse relationship between incubation time and misfolded prion accumulation, neuroinflammation, and autophagy. American Journal of Pathology. 190(7):1461-1473. https://doi.org/10.1016/j.ajpath.2020.03.006.
DOI: https://doi.org/10.1016/j.ajpath.2020.03.006

Interpretive Summary: Cases of bovine spongiform encephalopathy (BSE) or mad cow disease can be subclassified into at least 3 distinct disease forms with the predominate form known as classical BSE and the others collectively referred to as atypical BSE. Atypical BSE can be further subdivided into H-type and L-type cases that are distinct from classical BSE and from each other. Both of the atypical BSE subtypes are believed to occur spontaneously, whereas classical BSE is spread through feeding contaminated meat and bone meal to cattle. In this study, we demonstrate that atypical BSEs, characterized by shorter incubation periods after experimental intracranial inoculation, present with greater accumulation of abnormal prion protein (the main disease marker of BSE) and inflammatory markers and decreased markers of autophagy, a mechanism of degradation that occurs within cells. This work suggests a link between incubation period, inflammation, and clearance of the abnormal prion protein and may lead to the identification of markers of disease that could be used for earlier diagnosis or targeted for treatment strategies. This work should be of interest to the dairy and beef industries and individuals working toward improved diagnostic and treatment strategies for the animal or human spongiform encephalopathies.

Technical Abstract: Neurodegenerative protein misfolding disorders result from aberrant folding and accumulation of specific proteins. Transmissibility distinguishes transmissible spongiform encephalopathies (TSEs) from other protein misfolding diseases. TSE strains variations can influence disease phenotypes such as host susceptibility, biochemical and immunohistochemical profiles, and incubation periods. Bovine spongiform encephalopathy (BSE) is a TSE that occurs in cattle and can be subdivided into three different strains: classical BSE, atypical high-type, and low-type BSE. Both H-type and L-type BSEs, have shorter incubation periods and, therefore, an accelerated disease progression when compared to classical BSE. 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 protein misfolding diseases. Due to the similarities between TSEs and other protein misfolding diseases, TSEs can be used to understand other proteinopathies. In this study, we used the differences between classical and atypical BSE as a model to identify the molecular factors associated with disease progression. The NLRP3 inflammasome is a critical component of the innate immune system that leads to release of IL-1ß (Interlukin-1ß), an important regulator of neuroinflammation in many protein misfolding diseases. Macroautophagy is an intracellular mechanism that plays an essential role in protein clearance and homeostasis. In this study, we use the retina as a model to investigate the relationship between disease incubation period, PrPSc accumulation, neuroinflammation, and changes in macroautophagy. We demonstrate that atypical BSEs, characterized by shorter incubation periods, present with greater accumulation of PrPSc, glial-cell activation, NLRP3 inflammasome activation, and decreased autophagy. Our work suggests a relationship between disease time course, neuroinflammation, and the autophagic stress response, that has not been previously reported. This work may help identify novel therapeutic biomarkers that can delay, reverse, or even prevent the progression of protein-misfolding diseases.