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Antioxidants & Redox Signaling Jun 2010Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several... (Review)
Review
Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating iron-induced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP(C)). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP(Sc) or loss of normal function of PrP(C) remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP(C) to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP(Sc) in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders.
Topics: Animals; Humans; Oxidation-Reduction; Prion Diseases; Prions
PubMed: 19803746
DOI: 10.1089/ars.2009.2628 -
Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain.Glia Nov 2022Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia...
Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates central nervous system (CNS) prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1r mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models. Csf1r mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1r mice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced phagocytosis of neuronal contents and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.
Topics: Animals; Astrocytes; Brain; Mice; Microglia; Prion Diseases; Prions
PubMed: 35852018
DOI: 10.1002/glia.24244 -
Brain : a Journal of Neurology Apr 2022Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data...
Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
Topics: Biomarkers; Creutzfeldt-Jakob Syndrome; Humans; Insomnia, Fatal Familial; Prion Diseases; Prion Proteins; Prions; alpha-Synuclein
PubMed: 35288744
DOI: 10.1093/brain/awab350 -
Alzheimer's Research & Therapy Jun 2022To elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification. (Review)
Review
BACKGROUND
To elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification.
METHODS
Global data of gPrDs presenting with FTD caused by prion protein gene mutations were collected from literature review and our records. Fifty-one cases of typical FTD and 136 cases of prion diseases admitted to our institution were included as controls. Clinical and ancillary data of the different groups were compared.
RESULTS
Forty-nine cases of gPrDs presenting with FTD were identified. Compared to FTD or prion diseases, gPrDs presenting with FTD were characterized by earlier onset age (median 45 vs. 61/60 years, P < 0.001, P < 0.001) and higher incidence of positive family history (81.6% vs. 27.5/13.2%, P < 0.001, P < 0.001). Furthermore, GPrDs presenting with FTD exhibited shorter duration (median 5 vs. 8 years) and a higher rate of parkinsonism (63.7% vs. 9.8%, P < 0.001), pyramidal signs (39.1% vs. 7.8%, P = 0.001), mutism (35.9% vs. 0%, P < 0.001), seizures (25.8% vs. 0%, P < 0.001), myoclonus (22.5% vs. 0%, P < 0.001), and hyperintensity on MRI (25.0% vs. 0, P < 0.001) compared to FTD. Compared to prion diseases, gPrDs presenting with FTD had a longer duration of symptoms (median 5 vs. 1.1 years, P < 0.001), higher rates of frontotemporal atrophy (89.7% vs. 3.3%, P < 0.001), lower rates of periodic short-wave complexes on EEG (0% vs. 30.3%, P = 0.001), and hyperintensity on MRI (25.0% vs. 83.0%, P < 0.001). The frequency of codon 129 Val allele in gPrDs presenting with FTD was significantly higher than that reported in the literature for gPrDs in the Caucasian and East Asian populations (33.3% vs. 19.2%/8.0%, P = 0.005, P < 0.001).
CONCLUSIONS
GPrDs presenting with FTD are characterized by early-onset, high incidence of positive family history, high frequency of the Val allele at codon 129, overlapping symptoms with prion disease and FTD, and ancillary features closer to FTD. PRNP mutations may be a rare cause in the FTD spectrum, and PRNP genotyping should be considered in patients with these features.
Topics: Codon; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Mutation; Prion Diseases; Prions
PubMed: 35768878
DOI: 10.1186/s13195-022-01033-4 -
Genetics in Medicine : Official Journal... Apr 2010Prion diseases are a rare group of fatal neurodegenerative disorders of humans and animals that manifest primarily as progressive dementia and ataxia. Unique to these... (Review)
Review
Prion diseases are a rare group of fatal neurodegenerative disorders of humans and animals that manifest primarily as progressive dementia and ataxia. Unique to these diseases is the prion, a misfolded isoform of the prion protein that can transmit disease from cell to cell or host to host by associating with, and transforming, normal prion protein into the misfolded isoform (the pathogenic scrapie-inducing form). Although the majority of cases occur on a sporadic basis, and rarely result from exposure to prions, such as mad cow disease, 10-15% are attributable to the presence of an autosomal dominant mutation of the prion protein gene (PRNP). Single base pair changes, or the insertion of one or more multiples of a 24 base pair repeat segment, make up the known sequence alterations of PRNP associated with genetic prion disease. The common polymorphic codon 129 of PRNP also plays an important and complex role in risk and phenotype of sporadic and genetic prion disease. This review will focus on the clinical and histopathologic features of the genetic prion diseases. Selected mutations will be highlighted as a way to illustrate general phenotype-genotype correlations.
Topics: Brain; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Genetic; Prion Diseases; Prion Proteins; Prions
PubMed: 20216075
DOI: 10.1097/GIM.0b013e3181cd7374 -
Prion 2009Identification of genes expressed in response to prion infection may elucidate biomarkers for disease, identify factors involved in agent replication, mechanisms of...
Identification of genes expressed in response to prion infection may elucidate biomarkers for disease, identify factors involved in agent replication, mechanisms of neuropathology and therapeutic targets. Although several groups have sought to identify gene expression changes specific to prion disease, expression profiles rife with cell population changes have consistently been identified. Cuprizone, a neurotoxicant, qualitatively mimics the cell population changes observed in prion disease, resulting in both spongiform change and astrocytosis. The use of cuprizone-treated animals as an experimental control during comparative expression profiling allows for the identification of transcripts whose expression increases during prion disease and remains unchanged during cuprizone-triggered neuropathology. In this study, expression profiles from the brains of mice preclinically and clinically infected with Rocky Mountain Laboratory (RML) mouse-adapted scrapie agent and age-matched controls were profiled using Affymetrix gene arrays. In total, 164 genes were differentially regulated during prion infection. Eighty-three of these transcripts have been previously undescribed as differentially regulated during prion disease. A 0.4% cuprizone diet was utilized as a control for comparative expression profiling. Cuprizone treatment induced spongiosis and astrocyte proliferation as indicated by glial fibrillary acidic protein (Gfap) transcriptional activation and immunohistochemistry. Gene expression profiles from brain tissue obtained from cuprizone-treated mice identified 307 differentially regulated transcript changes. After comparative analysis, 17 transcripts unaffected by cuprizone treatment but increasing in expression from preclinical to clinical prion infection were identified. Here we describe the novel use of the prion disease mimetic, cuprizone, to control for cell population changes in the brain during prion infection.
Topics: Animals; Astrocytes; Cuprizone; Gene Expression Profiling; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microarray Analysis; Monoamine Oxidase Inhibitors; PrPSc Proteins; Prion Diseases
PubMed: 19535908
DOI: 10.4161/pri.3.2.9059 -
Viruses Sep 2021Genetic prion disease accounts for 10-15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an...
Genetic prion disease accounts for 10-15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt-Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt-Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt-Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt-Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.
Topics: Aged; Aged, 80 and over; Alleles; Brain; Creutzfeldt-Jakob Syndrome; Female; Humans; Male; Methionine; Middle Aged; Mutagenesis, Insertional; Oligopeptides; Prion Diseases; Prion Proteins; Prions
PubMed: 34578375
DOI: 10.3390/v13091794 -
Viruses Jun 2022Chronic wasting disease (CWD) is a prion disease affecting several species of captive and free-ranging cervids. In the past few decades, CWD has been spreading... (Review)
Review
Chronic wasting disease (CWD) is a prion disease affecting several species of captive and free-ranging cervids. In the past few decades, CWD has been spreading uncontrollably, mostly in North America, resulting in a high increase of CWD incidence but also a substantially higher number of geographical regions affected. The massive increase in CWD poses risks at several levels, including contamination of the environment, transmission to animals cohabiting with cervids, and more importantly, a putative transmission to humans. In this review, I will describe the mechanisms and routes responsible for the efficient transmission of CWD, the strain diversity of natural CWD, its spillover and zoonotic potential and strategies to minimize the CWD threat.
Topics: Animals; Deer; Humans; North America; Prion Diseases; Prions; Wasting Disease, Chronic
PubMed: 35891371
DOI: 10.3390/v14071390 -
Biomolecules Feb 2021The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer's disease (Aβ... (Review)
Review
The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer's disease (Aβ and tau), Parkinson's disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Creutzfeldt-Jakob Syndrome; Humans; Mice; Neurodegenerative Diseases; Phenotype; Plaque, Amyloid; Prion Diseases; Prion Proteins; Prions; Protein Denaturation; Protein Folding; alpha-Synuclein; tau Proteins
PubMed: 33540845
DOI: 10.3390/biom11020207 -
Current Issues in Molecular Biology 2020Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in... (Review)
Review
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, camel spongiform encephalopathy (CSE) in camels and chronic wasting disease (CWD) in cervids. A key event in prion diseases is the conversion of the cellular, host-encoded prion protein (PrPC) to its abnormal isoform (PrPSc) predominantly in the central nervous system of the infected host (Aguzzi et al., 2004). These diseases are transmissible under some circumstances, but unlike other transmissible disorders, prion diseases can also be caused by mutations in the host gene. The mechanism of prion spread among sheep and goats that develop natural scrapie is unknown. CWD, transmissible mink encephalopathy (TME), BSE, feline spongiform encephalopathy (FSE), and exotic ungulate encephalopathy (EUE) are all thought to occur after the consumption of prion-infected material. Most cases of human prion disease occur from unknown reasons, and greater than 20 mutations in the prion protein (PrP) gene may lead to inherited prion disease. In other instances, prion diseases are contracted by exposure to prion infectivity. These considerations raise the question of how a mere protein aggregate can bypass mucosal barriers, circumvent innate and adoptive immunity, and traverse the blood-brain barrier to give rise to brain disease. Here, we will briefly introduce a few topics in current prion studies.
Topics: Alzheimer Disease; Animals; Food Safety; Humans; Huntington Disease; Inflammation; Parkinson Disease; Prion Diseases; Prions; Proteostasis Deficiencies; Risk Factors; Transfusion Reaction
PubMed: 31559970
DOI: 10.21775/cimb.036.063