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Neuropathology : Official Journal of... Oct 2020This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt-Jakob disease (CJD). In CJD, we can... (Review)
Review
This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt-Jakob disease (CJD). In CJD, we can speculate on the pathological onset region to some degree in reference to the clinical symptoms and magnetic resonance imaging findings. Although relating the Braak hypothesis to prion disease is not straightforward, the following could be proposed based on experimental and previously reported case observations. Pathogenic abnormal prion protein (PrP) deposition in the central nervous system (CNS) probably begins several months or years before clinical symptom onset, signifying the potentiality of a preclinical stage, similar to α-synuclein deposition in Parkinson's disease (PD) and amyloid-β/tau deposition in Alzheimer's disease (AD). Unlike in PD and AD, the initial clinical symptoms of CJD vary by case, and thus the onset lesions must also be various and multiple in the CNS. Based on the pathological findings, particularly of PrP deposition extensively observed in the CNS gray matter of autopsy cases, it could be speculated that in the early disease stage, including the preclinical stage, abnormal PrP spreads from the onset region without directionality or hierarchy. Because each CNS region shows either vulnerability to or resistance against PrP deposition and pathological progression in prion disease, the lesion distribution shows system degeneration. Although pathologically combined cases of type 1 and type 2 PrP patterns are often recognized, type 1 and type 2 PrP patterns must never shift toward each other during the disease course; in other words, the original type of PrP deposition in each region presumably remains unchanged in each case. According to the several observations and corresponding speculations, there are at least partial similarities between prion disease and protein propagation, as explained by the Braak hypothesis, in terms of pathological lesion progression, but several noted contradictions preclude the hypothesis from comprehensively accounting for prion disease.
Topics: Animals; Brain; Creutzfeldt-Jakob Syndrome; Humans; Models, Neurological; Neurons; Prion Diseases
PubMed: 32363728
DOI: 10.1111/neup.12654 -
Cell and Tissue Research Apr 2023Epigenetics, meaning the variety of mechanisms underpinning gene regulation and chromatin states, plays a key role in normal development as well as in disease initiation... (Review)
Review
Epigenetics, meaning the variety of mechanisms underpinning gene regulation and chromatin states, plays a key role in normal development as well as in disease initiation and progression. Epigenetic mechanisms like alteration of DNA methylation, histone modifications, and non-coding RNAs, have been proposed as biomarkers for diagnosis, classification, or monitoring of responsiveness to treatment in many diseases. In prion diseases, the profound associations with human aging, the effects of cell type and differentiation on in vitro susceptibility, and recently identified human risk factors, all implicate causal epigenetic mechanisms. Here, we review the current state of the art of epigenetics in prion diseases and its interaction with genetic determinants. In particular, we will review recent advances made by several groups in the field profiling DNA methylation and microRNA expression in mammalian prion diseases and the potential for these discoveries to be exploited as biomarkers.
Topics: Animals; Humans; Epigenesis, Genetic; DNA Methylation; Biomarkers; Prion Diseases; Gene Expression; Mammals
PubMed: 35307791
DOI: 10.1007/s00441-022-03603-2 -
Cell and Tissue Research Apr 2023The properties of infectious prions and the pathology of the diseases they cause are dependent upon the unique conformation of each prion strain. How the pathology of... (Review)
Review
The properties of infectious prions and the pathology of the diseases they cause are dependent upon the unique conformation of each prion strain. How the pathology of prion disease correlates with different strains and genetic backgrounds has been investigated via in vivo assays, but how interactions between specific prion strains and cell types contribute to the pathology of prion disease has been dissected more effectively using in vitro cell lines. Observations made through in vivo and in vitro assays have informed each other with regard to not only how genetic variation influences prion properties, but also how infectious prions are taken up by cells, modified by cellular processes and propagated, and the cellular components they rely on for persistent infection. These studies suggest that persistent cellular infection results from a balance between prion propagation and degradation. This balance may be shifted depending upon how different cell lines process infectious prions, potentially altering prion stability, and how fast they can be transported to the lysosome. Thus, in vitro studies have given us a deeper understanding of the interactions between different prions and cell types and how they may influence prion disease phenotypes in vivo.
Topics: Humans; Prions; Prion Diseases; Cell Line
PubMed: 35107622
DOI: 10.1007/s00441-021-03572-y -
Neurochemistry International Nov 2019The cellular prion protein (PrP) is a medium-sized glycoprotein, attached to the cell surface by a glycosylphosphatidylinositol anchor. PrP is encoded by a single-copy... (Review)
Review
The cellular prion protein (PrP) is a medium-sized glycoprotein, attached to the cell surface by a glycosylphosphatidylinositol anchor. PrP is encoded by a single-copy gene, PRNP, which is abundantly expressed in the central nervous system and at lower levels in non-neuronal cells, including those of the immune system. Evidence from experimental knockout of PRNP in rodents, goats, and cattle and the occurrence of a nonsense mutation in goat that prevents synthesis of PrP, have shown that the molecule is non-essential for life. Indeed, no easily recognizable phenotypes are associate with a lack of PrP, except the potentially advantageous trait that animals without PrP cannot develop prion disease. This is because, in prion diseases, PrP converts to a pathogenic "scrapie" conformer, PrP, which aggregates and eventually induces neurodegeneration. In addition, endogenous neuronal PrP serves as a toxic receptor to mediate prion-induced neurotoxicity. Thus, PrP is an interesting target for treatment of prion diseases. Although loss of PrP has no discernable effect, alteration of its normal physiological function can have very harmful consequences. It is therefore important to understand cellular processes involving PrP, and research of this topic has advanced considerably in the past decade. Here, we summarize data that indicate the role of PrP in modulating immune signaling, with emphasis on neuroimmune crosstalk both under basal conditions and during inflammatory stress.
Topics: Animals; Cattle; Humans; Neuroimmunomodulation; Neurons; PrPC Proteins; Prion Diseases; Prion Proteins; Proteolysis
PubMed: 30448564
DOI: 10.1016/j.neuint.2018.11.010 -
BMB Reports Dec 2023Numerous studies have investigated the cellular prion protein (PrP) since its discovery. These investigations have explained that its structure is predominantly composed... (Review)
Review
Numerous studies have investigated the cellular prion protein (PrP) since its discovery. These investigations have explained that its structure is predominantly composed of alpha helices and short beta sheet segments, and when its abnormal scrapie isoform (PrP) is infected, PrP transforms the PrP, leading to prion diseases, including Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle. Given its ubiquitous distribution across a variety of cellular types, the PrP manifests a diverse range of biological functions, including cell-cell adhesion, neuroprotection, signalings, and oxidative stress response. PrP is also expressed in immune tissues, and its functions in these tissues include the activation of immune cells and the formation of secondary lymphoid tissues, such as the spleen and lymph nodes. Moreover, high expression of PrP in immune cells plays a crucial role in the pathogenesis of prion diseases. In addition, it affects inflammation and the development and progression of cancer via various mechanisms. In this review, we discuss the studies on the role of PrP from various immunological perspectives. [BMB Reports 2023; 56(12): 645-650].
Topics: Humans; Animals; Cattle; Prion Proteins; Prions; Prion Diseases; Encephalopathy, Bovine Spongiform; Immune System
PubMed: 37817440
DOI: 10.5483/BMBRep.2023-0151 -
Molecular Neurobiology Jun 2022Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the...
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.
Topics: Acute-Phase Proteins; Alzheimer Disease; Animals; Brain; Creutzfeldt-Jakob Syndrome; Humans; Mice; Neurodegenerative Diseases; Prion Diseases; Prions; Serpins
PubMed: 35416570
DOI: 10.1007/s12035-022-02817-3 -
International Journal of Molecular... Nov 2023Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy...
Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP as a cell model for prion diseases. We examined the role of PHB2 in PrP-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP, whereas the overexpression of PHB2 alleviated PrP neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP-treated neurons and protects neurons against the neurotoxicity of the prion peptide.
Topics: Animals; Rats; Mitophagy; Neurotoxicity Syndromes; Peptides; Prion Diseases; Prions; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 37958902
DOI: 10.3390/ijms242115919 -
International Journal of Molecular... Jun 2022Prion diseases are a group of devastating neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD) in humans, and scrapie and bovine spongiform...
Prion diseases are a group of devastating neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD) in humans, and scrapie and bovine spongiform encephalopathy (BSE) in animals [...].
Topics: Animals; Brain; Cattle; Creutzfeldt-Jakob Syndrome; Encephalopathy, Bovine Spongiform; Prion Diseases; Prions; Scrapie; Sheep
PubMed: 35742934
DOI: 10.3390/ijms23126490 -
Communicable Diseases Intelligence... Jun 2023Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry...
Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2022. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prospective Studies; Disease Notification; Australia; COVID-19; SARS-CoV-2; Prion Diseases
PubMed: 37357180
DOI: 10.33321/cdi.2023.47.37 -
Nature Communications Dec 2023The self-templating nature of prions plays a central role in prion pathogenesis and is associated with infectivity and transmissibility. Since propagation of...
The self-templating nature of prions plays a central role in prion pathogenesis and is associated with infectivity and transmissibility. Since propagation of proteopathic seeds has now been acknowledged a principal pathogenic process in many types of dementia, more insight into the molecular mechanism of prion replication is vital to delineate specific and common disease pathways. By employing highly discriminatory anti-PrP antibodies and conversion-tolerant PrP chimera, we here report that de novo PrP conversion and formation of fibril-like PrP aggregates are distinct in mechanistic and kinetic terms. De novo PrP conversion occurs within minutes after infection at two subcellular locations, while fibril-like PrP aggregates are formed exclusively at the plasma membrane, hours after infection. Phenotypically distinct pools of abnormal PrP at perinuclear sites and the plasma membrane show differences in N-terminal processing, aggregation state and fibril formation and are linked by exocytic transport via synaptic and large-dense core vesicles.
Topics: Humans; Prion Proteins; Prions; Cell Line; Cell Membrane; Muscle Fibers, Skeletal; Prion Diseases
PubMed: 38102121
DOI: 10.1038/s41467-023-43961-1