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Cold Spring Harbor Perspectives in... Jan 2017Human prion diseases are rare neurodegenerative diseases that have become the subject of public and scientific interest because of concerns about interspecies... (Review)
Review
Human prion diseases are rare neurodegenerative diseases that have become the subject of public and scientific interest because of concerns about interspecies transmission and the unusual biological properties of the causal agents: prions. These diseases are unique in that they occur in sporadic, hereditary, and infectious forms that are characterized by an extended incubation period between exposure to infection and the development of clinical illness. Silent infection can be present in peripheral tissues during the incubation period, which poses a challenge to public health, especially because prions are relatively resistant to standard decontamination procedures. Despite intense research efforts, no effective treatment has been developed for human prion diseases, which remain uniformly fatal.
Topics: Animals; Brain; Europe; Humans; Magnetic Resonance Imaging; Mice; Prion Diseases; Prion Proteins
PubMed: 27793965
DOI: 10.1101/cshperspect.a024364 -
Cell and Tissue Research Apr 2023Prion diseases are incurable, infectious and fatal neurodegenerative diseases that affect both humans and animals. The pathogenesis of prion disease involves the... (Review)
Review
Prion diseases are incurable, infectious and fatal neurodegenerative diseases that affect both humans and animals. The pathogenesis of prion disease involves the misfolding of the cellular prion protein, PrP, to a disease-causing conformation, PrP, in the brain. The exact mechanism of conversion of PrP to PrP is not clear; however, there are numerous studies supporting that this process of misfolding requires the association of PrP with lipid raft domains of the plasma membrane. An increase in the cellular cholesterol content with prion infection has been observed in both in vivo and in vitro studies. As cholesterol is critical for the formation of lipid rafts, on the one hand, this increase may be related to, or aiding in, the process of prion conversion. On the other hand, increased cholesterol levels may affect neuronal viability. Here, we discuss current literature on the underlying mechanisms and potential consequences of elevated neuronal cholesterol in prion infection and advancements in prion disease therapeutics targeting brain cholesterol homeostasis.
Topics: Animals; Humans; Prions; PrPSc Proteins; Prion Diseases; Prion Proteins; Cholesterol
PubMed: 35821439
DOI: 10.1007/s00441-022-03669-y -
Cold Spring Harbor Perspectives in... Nov 2017The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial... (Review)
Review
The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia, constitute ∼10%-15% of all PrP prion disease cases in humans. Attempts to generate animal models of these disorders using transgenic mice expressing mutant PrP have produced variable results. Although many lines of mice develop spontaneous signs of neurological illness with accompanying prion disease-specific neuropathological changes, others do not. Furthermore, demonstrating the presence of protease-resistant PrP species and prion infectivity-two of the hallmarks of the PrP prion disorders-in the brains of spontaneously sick mice has proven particularly challenging. Here, we review the progress that has been made toward developing accurate mouse models of the inherited PrP prion disorders.
Topics: Animals; Brain; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Mutation; Prion Diseases; Prion Proteins
PubMed: 28096244
DOI: 10.1101/cshperspect.a027151 -
Acta Neuropathologica Feb 2018The essential role of the cellular prion protein (PrP) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that... (Review)
Review
The essential role of the cellular prion protein (PrP) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that PrP may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease. Although the pathological roles of PrP have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrP in a diverse range of nervous system-related activities that include a key role in the maintenance of peripheral nerve myelination as well as a general ability to protect against neurotoxic stimuli. Thus, the function of PrP may be multifaceted, with different cell types taking advantage of unique aspects of its biology. Deciphering the cellular function(s) of PrP and the consequences of its absence is not simply an academic curiosity, since lowering PrP levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease. In this review, we outline the various approaches that have been employed in an effort to uncover the physiological and pathological functions of PrP. While these studies have revealed important clues about the biology of the prion protein, the precise reason for PrP's existence remains enigmatic.
Topics: Animals; Humans; Nervous System; PrPC Proteins; Prion Diseases
PubMed: 29151170
DOI: 10.1007/s00401-017-1790-y -
ILAR Journal 2015Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal protein-misfolding neurodegenerative diseases. TSEs have been described in several species,... (Review)
Review
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal protein-misfolding neurodegenerative diseases. TSEs have been described in several species, including bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME) in mink, and Kuru and Creutzfeldt-Jakob disease (CJD) in humans. These diseases are associated with the accumulation of a protease-resistant, disease-associated isoform of the prion protein (called PrP(Sc)) in the central nervous system and other tissues, depending on the host species. Typically, TSEs are acquired through exposure to infectious material, but inherited and spontaneous TSEs also occur. All TSEs share pathologic features and infectious mechanisms but have distinct differences in transmission and epidemiology due to host factors and strain differences encoded within the structure of the misfolded prion protein. The possibility that BSE can be transmitted to humans as the cause of variant Creutzfeldt-Jakob disease has brought attention to this family of diseases. This review is focused on the TSEs of livestock: bovine spongiform encephalopathy in cattle and scrapie in sheep and goats.
Topics: Animals; Cattle; Encephalopathy, Bovine Spongiform; Goats; Livestock; Prion Diseases; Prions; Proteostasis Deficiencies; Sheep
PubMed: 25991695
DOI: 10.1093/ilar/ilv008 -
Cells Sep 2022Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease... (Review)
Review
Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrP), into its disease-associated isoform PrP. Besides the aggregation and deposition of misfolded PrP, prion diseases are characterized by spongiform lesions and the activation of astrocytes and microglia. Microglia are the innate immune cells of the brain. Activated microglia and astrocytes represent a common pathological feature in neurodegenerative disorders. The role of activated microglia has already been studied in prion disease mouse models; however, it is still not fully clear how they contribute to disease progression. Moreover, the role of microglia in human prion diseases has not been thoroughly investigated thus far, and specific molecular pathways are still undetermined. Here, we review the current knowledge on the different roles of microglia in prion pathophysiology. We discuss microglia markers that are also dysregulated in other neurodegenerative diseases including microglia homeostasis markers. Data on murine and human brain tissues show that microglia are highly dysregulated in prion diseases. We highlight here that the loss of homeostatic markers may especially stand out.
Topics: Animals; Homeostasis; Humans; Mice; Microglia; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions; Protein Isoforms
PubMed: 36230910
DOI: 10.3390/cells11192948 -
Journal of Alzheimer's Disease : JAD 2018Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to... (Review)
Review
Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer's disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the 'bed-to-bench-and-back' research model.
Topics: Alzheimer Disease; Animals; Humans; Prion Diseases; Translational Research, Biomedical
PubMed: 29172000
DOI: 10.3233/JAD-170770 -
Open Veterinary Journal 2021Animal prion diseases are a group of neurodegenerative, transmissible, and fatal disorders that affect several animal species. The causative agent, prion, is a misfolded... (Review)
Review
Animal prion diseases are a group of neurodegenerative, transmissible, and fatal disorders that affect several animal species. The causative agent, prion, is a misfolded isoform of normal cellular prion protein, which is found in cells with higher concentration in the central nervous system. This review explored the sources of infection and different natural transmission routes of animal prion diseases in susceptible populations. Chronic wasting disease in cervids and scrapie in small ruminants are prion diseases capable of maintaining themselves in susceptible populations through horizontal and vertical transmission. The other prion animal diseases can only be transmitted through food contaminated with prions. Bovine spongiform encephalopathy (BSE) is the only animal prion disease considered zoonotic. However, due to its inability to transmit within a population, it could be controlled. The emergence of atypical cases of scrapie and BSE, even the recent report of prion disease in camels, demonstrates the importance of understanding the transmission routes of prion diseases to take measures to control them and to assess the risks to human and animal health.
Topics: Animals; Cattle; Cattle Diseases; Disease Susceptibility; Encephalopathy, Bovine Spongiform; Prion Diseases; Prions; Scrapie; Sheep; Sheep Diseases
PubMed: 35070868
DOI: 10.5455/OVJ.2021.v11.i4.23 -
Expert Review of Proteomics Apr 2015Prion diseases are a heterogeneous class of fatal neurodegenerative disorders associated with misfolding of host cellular prion protein (PrP(C)) into a pathological... (Review)
Review
Prion diseases are a heterogeneous class of fatal neurodegenerative disorders associated with misfolding of host cellular prion protein (PrP(C)) into a pathological isoform, termed PrP(Sc). Prion diseases affect various mammals, including humans, and effective treatments are not available. Prion diseases are distinguished from other protein misfolding disorders - such as Alzheimer's or Parkinson's disease - in that they are infectious. Prion diseases occur sporadically without any known exposure to infected material, and hereditary cases resulting from rare mutations in the prion protein have also been documented. The mechanistic underpinnings of prion and other neurodegenerative disorders remain poorly understood. Various proteomics techniques have been instrumental in early PrP(Sc) detection, biomarker discovery, elucidation of PrP(Sc) structure and mapping of biochemical pathways affected by pathogenesis. Moving forward, proteomics approaches will likely become more integrated into the clinical and research settings for the rapid diagnosis and characterization of prion pathogenesis.
Topics: Animals; Biomarkers; Humans; Prion Diseases; Prions; Proteomics
PubMed: 25795148
DOI: 10.1586/14789450.2015.1019481 -
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