Molecular Mechanisms of Prion Protein Amyloid Formation

National Institute Of Allergy And Infectious Diseases

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Abstract

Transmissible spongiform encephalopathies (TSEs or prion diseases) are a group of rare neurodegenerative diseases which include scrapie in sheep, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in mule deer and elk. In humans, the most common type of prion disease is Creutzfeldt-Jakob disease (CJD) which can occur in several forms. Sporadic CJD (sCJD) makes up the majority of CJD cases and occurs randomly at an incidence of 1-2 per million people worldwide. Iatrogenic CJD (iCJD) is associated with exposure to prion contaminated medical instruments or products while familial CJD (fCJD) is associated with mutations in the prion protein gene. 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. PrPSc can be deposited in the brain as either diffuse amyloid negative deposits or as dense amyloid positive deposits. For reasons that are not yet clear, amyloid forms of prion disease appear to be less transmissible than non-amyloid forms. Furthermore, it is not known if prion diseases where PrPSc is deposited primarily as amyloid follow the same pathogenic processes as prion diseases where PrPSc is primarily deposited as non-amyloid. Multiple studies in different mouse models have shown that amyloid formed from amyloid beta (Aβ) protein, alpha synuclein, and tau also propagate via prion-like mechanisms and spread from cell-to-cell (e.g. Science 313: 1781-1784 (2006), Nat Cell Biol 11: 909-913 (2009), J Exp Med 209: 975-986 (2012)). Based on these data, it has been suggested that amyloid formation in neurodegenerative proteinopathies such as Alzheimer’s Disease (AD) and Parkinson’s disease (PD) occurs via prion-like mechanisms and that proteins such as AD-associated Aβ may also be transmissible, infectious prions. Co-deposition of misfolded proteins during neurodegeneration, such as the co-localization of PrPSc and Aβ to plaques in some cases of sCJD (ACTA Neuropathol 96:116-122 (1998)), also suggest that interactions between these proteins could contribute to disease pathogenesis. Laboratory models of prion infection therefore represent a way of studying prion and prion-like mechanisms of disease that can potentially be applied to other neurodegenerative diseases triggered by misfolded proteins. We are interested in understanding the molecular mechanisms underlying PrP amyloid formation and have begun to approach this issue using both in vitro and in vivo model systems. This project focuses primarily on 1) understanding how protein aggregation and disaggregation are controlled by the cell and, 2) understanding the pathways of PrP amyloid formation and spread. Since PrPSc formation and spread appear to be mechanistically similar to the formation and spread of amyloid in other neurodegenerative diseases, the results of our prion studies will likely be broadly applicable to other diseases of protein misfolding and deposition. The ordered aggregation of PrPSc, Aβ, and other amyloid proteins is thought to be critical to the pathogenesis of neurodegenerative protein misfolding diseases such as prion disease and AD. However, the processes by which these aggregates form and the mechanisms by which the cell can degrade them remains poorly understood. In earlier studies of how prions interact with cells, we showed that the uptake and disaggregation of prions varied by prion strain (Annual Report 2013 and 2014), suggesting that the composition of PrPSc aggregates differed between strains. A Research Fellow in the lab, Dr. Daniel Shoup, has demonstrated that the sizes and stabilities of PrPSc aggregates change during cellular uptake and degradation and that these changes vary with the prion strain, potentially impacting the ability of a given prion strain to infect cells (Annual Report 2021). More recently, Dr. Shoup was able to monitor how the cell tries to unfold and degrade prions during the initial stages of prion infection. His work suggests that the ability of an individual prion strain to infect a cell may correlate with its ability to protect its core structure from destabilization and degradation by cellular processes (Annual Report 2023 and 2024). We have discovered that prion aggregates have different sizes and stabilities that may affect their ability to infect a cell and replicate (Annual Report 2021). In 2025, Dr. Shoup completed studies as part of a collaboration with Dr. Byron Caughey’s laboratory to determine if prion aggregates can be disassembled into replication competent dimeric and/or tetrameric prion aggregates. A manuscript based on this work with Dr. Shoup as first author was published in 2025. Overall, Dr. Shoup’s work provides mechanistic insights into how large aggregates of misfolded protein may replicate and spread not only in prion diseases, but also in other protein misfolding neurodegenerative diseases such as AD and PD. The most common form of human prion disease, sCJD, is thought to arise from the spontaneous conversion of PrPC into PrPSc. However, what triggers this spontaneous misfolding event is unknown. In 2025, using cell-based systems developed in our Section, Dr. Shoup has begun preliminary studies exploring how PrPC may be induced to misfold into PrPSc by exposure to different chemicals and proteins. These studies will address the origins and potential risk factors for sCJD, both critical and long-standing knowledge gaps in the field.