Molecular Genetics Of Scrapie Pathogenesis

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

Transmissible spongiform encephalopathies (TSEs or prion diseases) are a group of rare neurodegenerative diseases which include sporadic Creutzfeldt-Jakob disease (sCJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in mule deer and elk. Prions can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding prion pathogenesis and developing effective therapeutics. The infectious agent of prion diseases is called a prion and is largely composed of an abnormally refolded, protease resistant form (PrPSc) of the normal, protease sensitive prion protein, PrPC. Susceptibility to infection can be influenced by amino acid homology between PrPC and PrPSc while structural differences between PrPSc molecules are believed to encode strain phenotypes. My laboratory, the TSE/Prion Molecular Biology Section (TPMBS) addresses different aspects of prion diseases at both the molecular and pathogenic level including: 1) identifying the earliest events which occur during prion infection, 2) defining the molecular pathways involved in prion-associated neurodegeneration, 3) determining the molecular basis of prion strains, 4) determining how PrPC sequence and post-translational modifications influence PrPSc formation and disease phenotype and, 5) development of effective prion therapeutics. Although there is an increasing body of work suggesting that mitochondrial dysfunction is important in neurodegenerative protein misfolding diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), the role of mitochondria in prion disease is poorly understood. We have found that mitochondrial pathways of apoptosis are involved in non-amyloid forms of prion disease (Annual Report 2014) and were the first to show that mitochondrial respiration is impaired in late-stage prion disease (Annual Report 2017). Consistent with PrPC potentially having an effect on mitochondrial function and/or health, we have also published data showing that PrPC is present in mouse brain mitochondria (Annual Report 2017). Changes in mitochondrial energy production and dynamics can lead to changes in mitochondrial health and the initiation of mitophagy. We have shown that regulation of mitochondrial energy production by the molecule SARM1, which breaks down NADH, is protective during prion infection and can slow disease progression (Annual Report 2022). In 2025, we completed analyzing data for a project showing that the effect of SARM1 on prion infection may be cell type and prion strain specific. These data complement other data from our lab showing that mice expressing a naturally occurring mutation that stabilizes an enzyme needed to synthesize NADH are fully susceptible to prion infection. These data suggest not only that degradation of NADH, rather than its synthesis, is more important in protecting against prion disease, but also that that the cell type infected by prions may be important in the role of mitochondrial dysfunction in prion disease. A manuscript describing these studies is in progress. Mitophagy is the process whereby damaged mitochondria are destroyed by the cell. We have found that the proteins PINK1 and Parkin, which are involved in a well-described pathway of mitophagy, exert a protective effect on prion infection (Annual Report 2024). In 2025, we also asked whether or not a protein that helps localize Parkin to the mitochondrial membrane to activate mitophagy was similarly protective. Currently, the data suggest that expression of this protein does not significantly impact prion disease. This project is ongoing and is in collaboration with Dr. Sonja Best’s laboratory. As another approach to look at how mitochondrial health may impact prion disease, in 2025 a post-doctoral IRTA in the lab, Dr. Aaron Held, initiated in vivo prion infection studies to determine whether or not two proteins involved in regulating mitochondrial health and the integrated stress response exert a protective effect during prion infection. This project is ongoing and is in collaboration with Dr. Derek Narendra of NINDS who developed some of the gene knockout mice being used. Our studies on the role of mitochondria in prion disease implicate regulation of mitochondrial energy production as a possible mediating factor for prion disease progression. Last year Dr. Jason Hollister, the TPMBS technician, initiated an in vivo study to determine whether or not changes in energy production by the cell associated with different diets could slow prion disease progression by reducing cellular stress and triggering autophagy, a mechanism by which the cells degrade prions. In 2025, Dr. Hollister continued to analyze tissues from this study by both western blot and immunohistochemistry to determine the pathological phenotype of prion disease in these mice. He has also begun the analysis of a large and complex metabolomics dataset in order to determine how different energy pathways may have been altered by prion infection. The results of this study will have significant implications for the impact of diet on neurodegenerative diseases and could lead to diet-based approaches to slowing the progression of neurodegeneration. In 2025, the Research Fellow in TPMB, Dr. Daniel Shoup, published a manuscript using an in vitro protein re-folding assay that he developed to study the interactions of different chaperones with infectious prions. His work shows for the first time that disassembly of infectious prions by chaperones can release prion particles that can induce the formation of new prions. Thus, in trying to degrade prions, the cell is actually increasing the number of infectious prions present. His data not only provide a mechanistic basis for prion replication and spread and but also suggest that therapeutic approaches seeking to increase the degradation and removal of PrPSc could inadvertently exacerbate disease. In 2025, Dr. Shoup also continued his project using a cell-based system that he developed to study the redox state of mitochondria during the initial stages of prion infection. He had previously shown that there are prion-dependent changes in the mitochondrial redox state. His work in 2025 suggests that lysosomal damage in response to prion infection precedes changes in mitochondrial redox state. These studies will help us to understand not only how PrPSc may directly or indirectly influence mitochondrial function but also how mitochondria respond to prion infection. In 2025, he submitted a manuscript based on this work and is currently doing new experiments for submission of a revised version of the manuscript. There are no effective therapeutics for either prophylactic or clinical treatment of prion infection. In 2025, a post-doctoral IRTA fellow in the lab, Dr. Aaron Held, continued studies that he designed to determine if inhibitors of protein transport and/or the unfolded protein response could inhibit the formation of infectious prions. As part of this work, he also plans to analyze how the cellular systems for trafficking of PrPC and other secretory proteins are affected by the accumulation of pathological protein aggregates such as PrPSc. Also in 2025, Dr. Held will initiate in vivo experiments using prion infected mice to determine if inhibitors of protein transport can inhibit prion disease. Dr. Held’s work addresses critical knowledge gaps in the field and could lead to new targets and approaches for anti-prion therapies. Almost half of patients with sCJD have visual symptoms. Consistent with this, PrPSc is found in the retina where prion-related damage has been observed, although the mechanism of retinal degeneration in prion disease is unknown. As part of a collaboration studying photoreceptor cell death during prion infection that was initiated in the laboratory of Dr. Bruce Chesebro (who has since retired), a new post-doctoral IRTA Fellow, Dr. Leah Varner, joined the lab in 2025. She has begun using mouse models of prion infection that are unique to our lab to 1) understand how infectious prions can alter retinal function and vision, 2) study the cells in the retina infected by prions and determine how they die and, 3) determine how the prion protein that makes infectious prions normally functions in the retina. Her work addresses critical knowledge gaps in the field and could lead to non-invasive, retinal based diagnostics for prion disease.