Novel Morphological Glial Alterations in the Spectrum of Prion Disease Types: A Focus on Common Findings

Human prion diseases are a group of rare fatal neurodegenerative diseases with sporadic, genetic, and acquired forms. They are neuropathologically characterized by pathological prion protein accumulation, neuronal death, and vacuolation. Classical immunological response has long been known not to play a major in prion diseases; however, gliosis is known to be a common feature although variable in extent and poorly described. In this investigation, astrogliosis and activated microglia in two brain regions were assessed and compared with non-neurologically affected patients in a representative sample across the spectrum of Creutzfeldt–Jakob disease (CJD) forms and subtypes in order to analyze the influence of prion strain on pathological processes. In this report, we choose to focus on features common to all CJD types rather than the diversity among them. Novel pathological changes in both glial cell types were found to be shared by all CJD types. Microglial activation correlated to astrogliosis. Spongiosis, but not pathological prion protein deposition, correlated to both astrogliosis and microgliosis. At the ultrastructural level, astrocytic glial filaments correlated with pathological changes associated with prion disease. These observations confirm that neuroglia play a prominent role in the neurodegenerative process of prion diseases, regardless of the causative prion type.

Download Full-text

Goats naturally devoid of PrPC are resistant to scrapie

Veterinary Research ◽

10.1186/s13567-019-0731-2 ◽

2020 ◽

Vol 51 (1) ◽

Cited By ~ 8

Author(s):

Øyvind Salvesen ◽

Arild Espenes ◽

Malin R. Reiten ◽

Tram T. Vuong ◽

Giulia Malachin ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Clinical Signs ◽

Brain Regions ◽

Post Inoculation ◽

Dairy Goats ◽

Peripheral Tissues ◽

Clinical Onset ◽

Natural Mutation

AbstractPrion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrPC) is converted into a pathological and infectious form (PrPSc) in these diseases. Transgenic knockout models have shown that PrPC is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPC synthesis. We inoculated 12 goats (4 PRNP+/+, 4 PRNP+/Ter, and 4 PRNPTer/Ter) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP+/+ goats and 773 dpi in PRNP+/Ter goats. PrPSc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrPSc was limited in peripheral organs, but all PRNP+/+ goats and 1 of 4 PRNP+/Ter goats were positive in head lymph nodes. The four PRNPTer/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPSc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrPC due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrPC levels.

Download Full-text

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 ◽

Transmissible Spongiform Encephalopathies ◽

Protein Accumulation ◽

Spongiform Encephalopathies ◽

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.

Download Full-text

Differential Accumulation of Misfolded Prion Strains in Natural Hosts of Prion Diseases

Viruses ◽

10.3390/v13122453 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2453

Author(s):

Zoe J. Lambert ◽

Justin J. Greenlee ◽

Eric D. Cassmann ◽

M. Heather West Greenlee

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Brain Regions ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Prion Strains ◽

Natural Hosts ◽

Different Strains

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of neurodegenerative protein misfolding diseases that invariably cause death. TSEs occur when the endogenous cellular prion protein (PrPC) misfolds to form the pathological prion protein (PrPSc), which templates further conversion of PrPC to PrPSc, accumulates, and initiates a cascade of pathologic processes in cells and tissues. Different strains of prion disease within a species are thought to arise from the differential misfolding of the prion protein and have different clinical phenotypes. Different strains of prion disease may also result in differential accumulation of PrPSc in brain regions and tissues of natural hosts. Here, we review differential accumulation that occurs in the retinal ganglion cells, cerebellar cortex and white matter, and plexuses of the enteric nervous system in cattle with bovine spongiform encephalopathy, sheep and goats with scrapie, cervids with chronic wasting disease, and humans with prion diseases. By characterizing TSEs in their natural host, we can better understand the pathogenesis of different prion strains. This information is valuable in the pursuit of evaluating and discovering potential biomarkers and therapeutics for prion diseases.

Download Full-text

Genetic human prion disease modelled in PrP transgenic Drosophila

Biochemical Journal ◽

10.1042/bcj20170462 ◽

2017 ◽

Vol 474 (19) ◽

pp. 3253-3267 ◽

Cited By ~ 3

Author(s):

Alana M. Thackray ◽

Alzbeta Cardova ◽

Hanna Wolf ◽

Lydia Pradl ◽

Ina Vorberg ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Principal Component ◽

Site Directed Mutagenesis ◽

Host Protein ◽

Therapeutic Interventions ◽

Proteinase K ◽

Human Prion Disease ◽

Transgenic Drosophila

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila. Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host.

Download Full-text

Prion protein and prion disease at a glance

Journal of Cell Science ◽

10.1242/jcs.245605 ◽

2021 ◽

Vol 134 (17) ◽

Author(s):

Caihong Zhu ◽

Adriano Aguzzi

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Neurodegenerative Disorders ◽

Prion Diseases ◽

Amyloid Β ◽

Cellular Prion Protein ◽

Future Studies ◽

Associated Proteins ◽

Main Component ◽

Conformational Conversion

ABSTRACT Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.

Download Full-text

The neuroepidemiology of human prion disease

Oxford Textbook of Neurologic and Neuropsychiatric Epidemiology ◽

10.1093/med/9780198749493.003.0035 ◽

2020 ◽

pp. 367-378

Author(s):

Patrick JM Urwin ◽

Anna M Molesworth

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Protein Misfolding ◽

Prion Diseases ◽

Prion Protein Gene ◽

Human Prion Disease ◽

Disease States ◽

Jakob Disease ◽

The Central Nervous System ◽

Sporadic Disease

Human prion diseases comprise a number of rare and fatal neurodegenerative conditions that result from the accumulation in the central nervous system of an abnormal form of a naturally occurring protein, called the prion protein. The diseases occur in genetic, sporadic, and acquired forms: genetic disease is associated with mutations in the prion protein gene (PRNP); sporadic disease is thought to result from a spontaneous protein misfolding event; acquired disease results from transmission of infection from an animal or another human. The potential transmissibility of the prion in any of these forms, either in disease states or during the incubation period, has implications for public health. Here we focus on Creutzfeldt-Jakob Disease (CJD), including variant Creutzfeldt-Jakob Disease (vCJD), although we will also discuss other forms of human prion disease.

Download Full-text

Structural effects of the highly protective V127 polymorphism on human prion protein

Communications Biology ◽

10.1038/s42003-020-01126-6 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Laszlo L. P. Hosszu ◽

Rebecca Conners ◽

Daljit Sangar ◽

Mark Batchelor ◽

Elizabeth B. Sawyer ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Structural Changes ◽

Prion Diseases ◽

Single Point ◽

Structural Basis ◽

Single Point Mutation ◽

Solution Dynamics ◽

Human Prion Protein ◽

Prion Transmission

AbstractPrion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.

Download Full-text

Prion Protein Expression Differences in Microglia and Astroglia Influence Scrapie-Induced Neurodegeneration in the Retina and Brain of Transgenic Mice

Journal of Virology ◽

10.1128/jvi.00865-07 ◽

2007 ◽

Vol 81 (19) ◽

pp. 10340-10351 ◽

Cited By ~ 31

Author(s):

Lisa Kercher ◽

Cynthia Favara ◽

James F. Striebel ◽

Rachel LaCasse ◽

Bruce Chesebro

Keyword(s):

Transgenic Mice ◽

Prion Protein ◽

Microglial Activation ◽

Prion Diseases ◽

Cell Types ◽

Mouse Strains ◽

Activation Markers ◽

Activated Microglia ◽

Morphological Criteria ◽

Scrapie Infection

ABSTRACT Activated microglia and astroglia are known to be involved in a variety of neurodegenerative diseases, including prion diseases. In the present experiments, we studied activation of astroglia and microglia after intraocular scrapie infection in transgenic mice expressing prion protein (PrP) in multiple cell types (tg7 mice) or in neurons only (tgNSE mice). In this model, scrapie infection and protease-resistant PrP deposition occurs in the retinas of both strains of mice, but retinal degeneration is observed only in tg7 mice. Our results showed that the retinas of tg7 and tgNSE mice both had astroglial activation with increased chemokine expression during the course of infection. However, only tg7 retinas exhibited strong microglial activation compared to tgNSE retinas, which showed little microglial activation by biochemical or morphological criteria. Therefore, microglial PrP expression might be required for scrapie-induced retinal microglial activation and damage. Furthermore, microglial activation preceded retinal neurodegeneration in tg7 mice, suggesting that activated microglia might contribute to the degenerative process, rather than being a response to the damage. Surprisingly, brain differed from retina in that an altered profile of microglial activation markers was upregulated, and the profiles in the two mouse strains were indistinguishable. Microglial activation in the brain was associated with severe brain vacuolation and neurodegeneration, leading to death. Thus, retinal and brain microglia appeared to differ in their requirements for activation, suggesting that different activation pathways occur in the two tissues.

Download Full-text

Prion disease

10.1093/med/9780199568741.003.0319 ◽

2018 ◽

Author(s):

Richard Knight

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Human Diseases ◽

Brain Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Structural Form ◽

Spongiform Encephalopathies ◽

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.

Download Full-text

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽

10.3390/pathogens9060482 ◽

2020 ◽

Vol 9 (6) ◽

pp. 482

Author(s):

Simote Foliaki ◽

Bradley Groveman ◽

Jue Yuan ◽

Ryan Walters ◽

Shulin Zhang ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Neurological Disorders ◽

Prion Diseases ◽

Three Dimensional ◽

Protein Isoforms ◽

Genetic Modifiers ◽

Neuronal Tissue ◽

Prion Infection ◽

E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

Download Full-text