Prion disease

Structural Form ◽

Spongiform Change ◽

Neurodegenerative Pathology

Prion diseases (also known as transmissible spongiform encephalopathies (TSEs)) affect animals and humans, although only the human diseases will be discussed in this chapter. Despite TSEs having somewhat disparate causes and effects, there are unifying features: TSEs are brain diseases with neurodegenerative pathology, which is typically associated with spongiform change, and, most characteristically, there is tissue deposition of an abnormal structural form of the prion protein. Some of the TSEs are naturally acquired infections and, while others are not, they are potentially transmissible in certain circumstances.

Reduced SOD2 expression does not influence prion disease course or pathology in mice

PLoS ONE ◽

10.1371/journal.pone.0259597 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0259597

Author(s):

Simote T. Foliaki ◽

Brent Race ◽

Katie Williams ◽

Chase Baune ◽

Bradley R. Groveman ◽

...

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Critical Role ◽

Long Term Potentiation ◽

Spongiform Encephalopathy ◽

Knock Out ◽

Spongiform Change ◽

Knock Out Mice

Prion diseases are progressive, neurodegenerative diseases affecting humans and animals. Also known as the transmissible spongiform encephalopathies, for the hallmark spongiform change seen in the brain, these diseases manifest increased oxidative damage early in disease and changes in antioxidant enzymes in terminal brain tissue. Superoxide dismutase 2 (SOD2) is an antioxidant enzyme that is critical for life. SOD2 knock-out mice can only be kept alive for several weeks post-birth and only with antioxidant therapy. However, this results in the development of a spongiform encephalopathy. Consequently, we hypothesized that reduced levels of SOD2 may accelerate prion disease progression and play a critical role in the formation of spongiform change. Using SOD2 heterozygous knock-out and litter mate wild-type controls, we examined neuronal long-term potentiation, disease duration, pathology, and degree of spongiform change in mice infected with three strains of mouse adapted scrapie. No influence of the reduced SOD2 expression was observed in any parameter measured for any strain. We conclude that changes relating to SOD2 during prion disease are most likely secondary to the disease processes causing toxicity and do not influence the development of spongiform pathology.

Prion disease and endoplasmic reticulum stress pathway correlations and treatment pursuits

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2017-0003 ◽

2017 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Tarah Satterfield ◽

Jessica Pritchett ◽

Sarah Cruz ◽

Kyeorda Kemp

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Cellular Prion Protein ◽

Protein Accumulation ◽

Unfolded Protein

AbstractBackground: Transmissible spongiform encephalopathies are a collection of rare neurodegenerative disorders characterized by loss of neuronal cells, astrocytosis, and plaque formation. The causative agent of these diseases is thought to be abnormally folded prions and is characterized by a conformational change from normal, cellular prion protein (PrPc) to the abnormal form (PrPTSE). Although, there is evidence that normal prion protein can contribute to these disorders. The unfolded protein response, a conserved series of pathways involved in resolving stress associated with unfolded protein accumulation in the Endoplasmic Reticulum (ER), has been shown to play a role in regulating the development of prion diseases. Methods: This review chose papers based on their relevance to current studies involved in prion protein synthesis and transformation, identifies various links between prion diseases and ER stress, and reports on current and potential treatments as they relate to ER stress and prion diseases. Conclusion: For the advancement of prion disease treatment, it is important to understand the mechanisms involved in prion formation, and ER stress is implicated in prion disease progression. Therefore, targeting the ER or pathways involved in response to stress in the ER may help us treat prion diseases.

Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

Biomolecular NMR Assignments ◽

10.1007/s12104-021-10005-y ◽

2021 ◽

Vol 15 (1) ◽

pp. 193-196

Author(s):

Máximo Sanz-Hernández ◽

Alfonso De Simone

Keyword(s):

Prion Protein ◽

Nmr Assignments ◽

Chemical Shifts ◽

Prion Diseases ◽

Random Coil ◽

Globular Domain ◽

Structural Elements ◽

Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

Animal Health Research Reviews ◽

10.1017/s1466252307001181 ◽

2006 ◽

Vol 7 (1-2) ◽

pp. 97-105 ◽

Cited By ~ 42

Author(s):

Scott P. Leach ◽

M. D. Salman ◽

Dwayne Hamar

Keyword(s):

Trace Elements ◽

Prion Protein ◽

Copper Ions ◽

Prion Diseases ◽

Normal Function ◽

Copper Binding ◽

Copper Manganese ◽

The Brain

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

Copper and prion diseases

Biochemical Society Transactions ◽

10.1042/bst0300742 ◽

2002 ◽

Vol 30 (4) ◽

pp. 742-745 ◽

Cited By ~ 16

Author(s):

D. R. Brown

Keyword(s):

Prion Protein ◽

Strong Evidence ◽

Prion Diseases ◽

Normal Brain ◽

Metal Metabolism ◽

Jakob Disease ◽

Anti Oxidant ◽

Experimental Mouse

Transmissible spongiform encephalopathies are diseases of animals and humans that are also termed prion diseases. These diseases are linked together because a normal brain glycoprotein termed the prion protein is converted to a readily detectable protease-resistant isoform. There is now strong evidence to suggest that apart from this difference in resistance a major difference between the isoforms is that the normal prion protein binds copper and has an anti-oxidant function. Brains from Creutzfeldt-Jakob disease patients and brains from mice with experimental mouse scrapie have been shown to have changes in the levels of both copper and manganese. There is growing evidence that links prion diseases to disturbances of metal metabolism.

Prion protein interconversions†

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2000.0765 ◽

2001 ◽

Vol 356 (1406) ◽

pp. 197-202 ◽

Cited By ~ 17

Author(s):

Byron Caughey

Keyword(s):

Neurodegenerative Diseases ◽

Prion Protein ◽

Prion Diseases ◽

Biological Parameters ◽

Lead Compounds ◽

Resistant Form

The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease–associated, protease–resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti–TSE drugs.

Creutzfeldt–Jakob disease surveillance in Australia: update to December 2017

Communicable Diseases Intelligence ◽

10.33321/cdi.2019.43.32 ◽

2019 ◽

Vol 43 ◽

Cited By ~ 1

Author(s):

Christiane Stehmann ◽

Shannon Sarros ◽

Matteo Senesi ◽

Victoria Lewis ◽

Marion Simpson ◽

...

Keyword(s):

Prion Disease ◽

Disease Surveillance ◽

Prion Diseases ◽

Annual Number ◽

Prospective Surveillance ◽

Surveillance Period ◽

Jakob Disease ◽

Neuropathological Examination

Nationwide surveillance of human prion diseases (also known as transmissible spongiform encephalopathies), the most common being Creutzfeldt–Jakob disease (CJD), is performed by the Australian National Creutzfeldt–Jakob Disease Registry (ANCJDR), based at the University of Melbourne. National surveillance encompasses the period since 1970, with prospective surveillance occurring from 1993 onwards. Over this prospective surveillance period considerable developments have occurred, especially in relation to pre-mortem diagnostics, the delineation of new disease subtypes and a heightened awareness of prion diseases in the health care setting. The surveillance practices of the ANCJDR have evolved and adapted accordingly. Since the ANCJDR began offering cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased to a maximum of 508 in 2017. The number of CSF test referrals in 2017 represents a 20% increase compared to that of 2016. In 2017, there was an overall stabilisation of the annual incidence rate of confirmed prion disease in Australia at expected levels; 72 persons with suspected human prion disease were added to the national register, with 72% of all suspected CJD cases undergoing neuropathological examination. The majority of the 72 suspected cases added to the register are as of 31 December 2017 still classified as “incomplete” (47 cases), while four cases were excluded by either detailed clinical follow-up (1 case) or neuropathological examination (3 cases); 19 cases were classified as definite and two as probable prion disease. No cases of variant CJD (vCJD) were confirmed.

Large-scale lipidomic profiling identifies novel potential biomarkers for prion diseases and highlights lipid raft-related pathways

Veterinary Research ◽

10.1186/s13567-021-00975-1 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Yong-Chan Kim ◽

Junbeom Lee ◽

Dae-Weon Lee ◽

Byung-Hoon Jeong

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Large Scale ◽

Right Hemisphere ◽

Prion Diseases ◽

Lipid Extraction ◽

Pathway Enrichment Analysis ◽

The Brain ◽

Potential Biomarkers

AbstractPrion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.

Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease

Journal of General Virology ◽

10.1099/vir.0.81615-0 ◽

2006 ◽

Vol 87 (7) ◽

pp. 2109-2114 ◽

Cited By ~ 97

Author(s):

Chad Johnson ◽

Jody Johnson ◽

Joshua P. Vanderloo ◽

Delwyn Keane ◽

Judd M. Aiken ◽

...

Keyword(s):

Prion Protein ◽

Chronic Wasting Disease ◽

Prion Diseases ◽

Genetic Barrier ◽

Wasting Disease ◽

Population Comparison ◽

Free Ranging ◽

The Impact

The primary sequence of the prion protein affects susceptibility to transmissible spongiform encephalopathies, or prion diseases, in mice, sheep and humans. The Prnp gene sequence of free-ranging, Wisconsin white-tailed deer was determined and the Prnp genotypes of chronic wasting disease (CWD)-positive and CWD-negative deer were compared. Six amino acid changes were identified, two of which were located in pseudogenes. Two alleles, a Q→K polymorphism at codon 226 and a single octapeptide repeat insertion into the pseudogene, have not been reported previously. The predominant alleles – wild-type (Q95, G96 and Q226) and a G96S polymorphism – comprised almost 98 % of the Prnp alleles in the Wisconsin white-tailed deer population. Comparison of the allelic frequencies in the CWD-positive and CWD-negative deer suggested that G96S and a Q95H polymorphism were linked to a reduced susceptibility to CWD. The G96S allele did not, however, provide complete resistance, as a CWD-positive G96S/G96S deer was identified. The G96S allele was also linked to slower progression of the disease in CWD-positive deer based on the deposition of PrPCWD in the obex region of the medulla oblongata. Although the reduced susceptibility of deer with at least one copy of the Q95H or G96S allele is insufficient to serve as a genetic barrier, the presence of these alleles may modulate the impact of CWD on white-tailed deer populations.

Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

Anais da Academia Brasileira de Ciências ◽

10.1590/0001-3765201520140712 ◽

2015 ◽

Vol 87 (2 suppl) ◽

pp. 1421-1434 ◽

Cited By ~ 1

Author(s):

CLAUDIA P. FIGUEIREDO ◽

NATALIA C. FERREIRA ◽

GISELLE F. PASSOS ◽

ROBSON DA COSTA ◽

FERNANDA S. NEVES ◽

...

Keyword(s):

Prion Protein ◽

Aromatic Compounds ◽

Prion Diseases ◽

Intraperitoneal Administration ◽

Neuroblastoma Cells ◽

Cellular Prion Protein ◽

Toxicological Evaluation ◽

Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.