Incubation periods of classical and atypical bovine spongiform encephalopathies (BSE) reflect an inverse relationship between PrPSc-associated 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: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/29/2019
Publication Date: 5/18/2019
Citation: Mammadova, N., West Greenlee, M.H., Moore, S.J., Sakaguchi, D.S., Greenlee, J.J. 2019. Incubation periods of classical and atypical bovine spongiform encephalopathies (BSE) reflect an inverse relationship between PrPSc-associated neuroinflammation and autophagy. Prion. 13. Article 242. https://doi.org/10.1080/19336896.2019.1615197.
DOI: https://doi.org/10.1080/19336896.2019.1615197

Interpretive Summary:

Technical Abstract: Neurodegenerative protein misfolding disorders are a group of diseases in both humans and animals with a similar mechanism of disease progression. These diseases, that include Alzheimer’s disease, Parkinson’s disease, chronic wasting disease, and bovine spongiform encephalopathy (BSE) result from aberrant folding and accumulation of disease specific proteins. Transmissible spongiform encephalopathies (TSEs) are diseases that result from improper folding and accumulation of the prion protein. Due to their transmissibility, TSEs are an important experimental model to study the basic pathobiology of all protein misfolding disorders. TSE strain variations can influence disease phenotypes such as host susceptibility, biochemical and immunohistochemical profiles, and incubation periods. BSE is a TSE that occurs in cattle that can be subdivided into three different strains: classical BSE, atypical high (H)-type, and atypical low (L)-type BSE. Both H-type and L-type BSEs, have shorter incubation periods after experimental inoculation and, therefore, an accelerated disease progression when compared to classical BSE. Currently, there is a lack of knowledge about the factors that influence accumulation of misfolded proteins and disease progression making this a key challenge for the development of therapies for protein misfolding diseases. 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. Here we used the retina and three brain regions 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 demonstrates 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 approaches that can delay or even prevent the progression of protein-misfolding diseases.