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Transmissible Spongiform Encephalopathies (TSE)

Prions and Prion-Like Proteins in Protein Misfolding Diseases

Prion and prion-like proteins are increasingly being recognized as causing neurodegenerative diseases. 1,2 The most well-known is the PRNP (prion protein) human gene coding for the major prion protein PrP (prion protein), also known as CD230. Disease-associated prion protein (PrPd, PrPsc) isoforms cause transmissible spongiform encephalopathies (TSEs), a group of progressive and fatal mammalian neurodegenerative diseases. Examples of TSEs include Creutzfeldt-Jakob disease (CJD) fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker disease (GSS) in humans. Examples of TSEs in animals include bovine spongiform encephalopathy (BSE) in cattle, also known as mad cow disease, scrapie in sheep and goats, and chronic wasting disease in deer.

The normal mature form of PrP (PrPc) is a cell-surface glycoprotein which is highly conserved among mammals. PrPc expression begins in embryogenesis and is predominantly expressed in neurons of the adult brain. PrPc is thought to be involved in the regulation of copper homeostasis; however, the biological function of PrPc remains to be fully elucidated. Most of the PrP research interest is focused on the PrPd (PrPsc) isoforms which are commonly called prions, because they cause disease.

PrPc is a glycosyl-phosphatidylionositol (GPI)-anchored cell surface membrane glycoprotein. In contrast, the pathogenic prion is a misfolded, aggregation prone protein which accumulates in the central nervous system (CNS). Prions are resistant to protease digestion, insoluble, and have a high content of beta-sheet structure. In contrast PrPc is a soluble protein which is low in beta-sheet, high in alpha-helices and highly susceptible to digestion by proteases.

Prions (proteinaceous infectious particle) are referred to as having infectious characteristics because a newly form prion acts as a self-perpetuating template to facilitate the spontaneous conversion of PrPc into prions. This results in the accumulation of toxin prion aggregates in the CNS, including the brain, eye and spinal cord, leading to neurodegeneration and TSE. There are spongiform changes in the brain, loss of neurons, synaptic dysfunction, and amyloid deposits. In some TSEs, prions precipitate in the tissues as amyloid plaques also known as prion amyloid aggregates. Prions have also been detected outside the CNS, including the blood, urine and lymphoid tissues. However the mechanisms of prion involvement in neurodegeneration and infectious TSE transmission, such as the development of a TSE following consumption of BSE-contaminated beef, are not completely defined.

The initial misfolding event of PrP leading to the formation of the prion with its aberrant conformation can be spontaneous or caused by mutations in the PRNP gene. Spontaneous conversion of wild-type PrP (aka PrPc) to a prion (aka PrPd) has been referred to as de novo prion generation/synthesis. 2 PRNP gene mutations have been described in familial CJD, FFI, and GSS. Prions gained extensive public awareness during the 1990's when the media drew attention to cases of mad cow disease transmitted by eating beef from BSE-infected cows. The US federal government prohibits the importation of certain animals and meat products where mad cow disease is known to be present. This ban is designed to prevent high-risk animals or products that could potentially be infected with prions from entering human, animal and pet food supply chains.

It has been suggested that similar mechanisms analogous to prion formation may exist for other proteins implicated in various protein misfolding-related diseases such as Parkinson's disease, Alzheimer's disease, amyotropic lateral sclerosis (ALS) and systemic amyloidosis. 1 These diseases and others which are associated with misfolded proteins has led to a proliferation of prion-related terms including prion-like, prion-related, propagon, and prionoid. Similarities in molecular mechanisms among misfolding-related diseases include the formation of aggregated proteins which are associated with or are known to have causal factors in disease progression. For example, aggregates of transactive response DNA binding protein 43 (TDP-43) and Cu-Zn superoxide dismutase (SOD-1) have been described in ALS. Likewise, alpha-synuclein aggregates are found in Parkinson's disease and the accumulation of amyloid beta peptides and tau are hallmarks of Alzheimer's disease. Although different proteins are involved in the various misfolding-related diseases, similarities include the formation of aggregated proteins which are associated with or are known to have causal factors in disease progression.

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  • 1. Erana H, Venegas V, Moreno J, Castilla J. Prion-like disorders and transmissible spongiform encephalopathies: An overview of the mechanistic features that are shared by the various disease-related misfolded proteins. 2016. BBRC http://dx.doi.org/10.1016/j.bbrc.2016.08.166
  • 2. Atkinson CJ, Zhang K, Munn AL, Wiegmans A et al. Prion protein scrapie and the normal cellular prion protein. 2015 Prion 10:1, 63-82. http://dx.doi.org/10.1080/19336896.2015.1110293

  • Transmissible Spongiform Encephalopathies (TSE)
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