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The Lancet. Neurology Mar 2021Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP). Effective therapeutics are currently not available and... (Review)
Review
Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrP seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.
Topics: Biomarkers; Creutzfeldt-Jakob Syndrome; Genetic Markers; Guidelines as Topic; Humans; Neuroimaging; Sensitivity and Specificity
PubMed: 33609480
DOI: 10.1016/S1474-4422(20)30477-4 -
Nature Reviews. Neurology Jun 2022Rapidly progressive dementias (RPDs) are a group of heterogeneous disorders that include immune-mediated, infectious and metabolic encephalopathies, as well as prion... (Review)
Review
Rapidly progressive dementias (RPDs) are a group of heterogeneous disorders that include immune-mediated, infectious and metabolic encephalopathies, as well as prion diseases and atypically rapid presentations of more common neurodegenerative diseases. Some of these conditions are treatable, and some must be diagnosed promptly because of their potential infectivity. Prion disease is considered to be the prototypical RPD, but over the past two decades, epidemiological reports and the identification of various encephalitis-mediating antibodies have led to a growing recognition of other encephalopathies as potential causes of rapid cognitive decline. Knowledge of RPD aetiologies, syndromes and diagnostic work-up protocols will help clinicians to establish an early, accurate diagnosis, thereby reducing morbidity and mortality, especially in immune-mediated and other potentially reversible dementias. In this Review, we define the syndrome of RPD and shed light on its different aetiologies and on secondary factors that might contribute to rapid cognitive decline. We describe an extended diagnostic procedure in the context of important differential diagnoses, discuss the utility of biomarkers and summarize potential treatment options. In addition, we discuss treatment options such as high-dose steroid therapy in the context of therapy and diagnosis in clinically ambiguous cases.
Topics: Brain Diseases; Dementia; Diagnosis, Differential; Disease Progression; Humans; Neurodegenerative Diseases; Prion Diseases
PubMed: 35508635
DOI: 10.1038/s41582-022-00659-0 -
International Journal of Molecular... Feb 2021Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various... (Review)
Review
Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various neurodegenerative conditions including prion diseases. Microglia play an overall neuroprotective role in prion disease, whereas reactive astrocytes with aberrant phenotypes propagate prions and contribute to prion-induced neurodegeneration. The existence of heterogeneous subpopulations and dual functions of microglia and astrocytes in prion disease make them potential targets for therapeutic intervention. A variety of neuroinflammation-related molecules are involved in prion pathogenesis. Therapeutics targeting neuroinflammation represents a novel approach to combat prion disease. Deciphering neuroinflammation in prion disease will deepen our understanding of pathogenesis of other neurodegenerative disorders.
Topics: Animals; Brain; Chemokines; Cytokines; Gliosis; Humans; Inflammation; Microglia; Phagocytosis; Prion Diseases; Toll-Like Receptors
PubMed: 33672129
DOI: 10.3390/ijms22042196 -
International Journal of Molecular... Jul 2021The principal pathogenic event in Parkinson's disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded... (Review)
Review
The principal pathogenic event in Parkinson's disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson's disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed.
Topics: Animals; Dopaminergic Neurons; Humans; Parkinson Disease; Prion Diseases; Protein Aggregates; alpha-Synuclein; tau Proteins
PubMed: 34360787
DOI: 10.3390/ijms22158022 -
Nature Medicine Feb 2024Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA))...
Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt-Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.
Topics: Young Adult; Humans; Child; Alzheimer Disease; Growth Hormone; Amyloid beta-Peptides; Creutzfeldt-Jakob Syndrome; Cerebral Amyloid Angiopathy; Brain; Prions; Cadaver; Iatrogenic Disease; Biomarkers
PubMed: 38287166
DOI: 10.1038/s41591-023-02729-2 -
Biomolecules Mar 2021Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human... (Review)
Review
Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrP) into a misfolded pathological isoform (PrP or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrP. Yet by an unknown mechanism, PrP can fold into different PrP conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrP are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD).
Topics: Animals; Cattle; Encephalopathy, Bovine Spongiform; Humans; Prion Diseases; Prion Proteins; Prions; Scrapie
PubMed: 33801117
DOI: 10.3390/biom11030466 -
Current Opinion in Neurobiology Feb 2022Despite being caused by a single protein, prion diseases are strikingly heterogenous. Individual prion variants, known as strains, possess distinct biochemical... (Review)
Review
Despite being caused by a single protein, prion diseases are strikingly heterogenous. Individual prion variants, known as strains, possess distinct biochemical properties, form aggregates with characteristic morphologies and preferentially seed certain brain regions, causing markedly different disease phenotypes. Strain diversity is determined by protein structure, post-translational modifications and the presence of extracellular matrix components, with single amino acid substitutions or altered protein glycosylation exerting dramatic effects. Here, we review recent advances in the study of prion strains and discuss how a deeper knowledge of the molecular origins of strain heterogeneity is providing a foundation for the development of anti-prion therapeutics.
Topics: Brain; Glycosylation; Humans; Phenotype; Prion Diseases; Prions
PubMed: 34416480
DOI: 10.1016/j.conb.2021.07.010 -
Cell and Tissue Research Apr 2023Human cerebral organoids are an exciting and novel model system emerging in the field of neurobiology. Cerebral organoids are spheres of self-organizing, neuronal... (Review)
Review
Human cerebral organoids are an exciting and novel model system emerging in the field of neurobiology. Cerebral organoids are spheres of self-organizing, neuronal lineage tissue that can be differentiated from human pluripotent stem cells and that present the possibility of on-demand human neuronal cultures that can be used for non-invasively investigating diseases affecting the brain. Compared with existing humanized cell models, they provide a more comprehensive replication of the human cerebral environment. The potential of the human cerebral organoid model is only just beginning to be elucidated, but initial studies have indicated that they could prove to be a valuable model for neurodegenerative diseases such as prion disease. The application of the cerebral organoid model to prion disease, what has been learned so far and the future potential of this model are discussed in this review.
Topics: Humans; Induced Pluripotent Stem Cells; Prion Diseases; Brain; Pluripotent Stem Cells; Organoids
PubMed: 35088182
DOI: 10.1007/s00441-022-03589-x -
Cell and Tissue Research Apr 2023Prion diseases are fatal neurodegenerative conditions of humans and various vertebrate species that are transmissible between individuals of the same or different... (Review)
Review
Prion diseases are fatal neurodegenerative conditions of humans and various vertebrate species that are transmissible between individuals of the same or different species. A novel infectious moiety referred to as a prion is considered responsible for transmission of these conditions. Prion replication is believed to be the cause of the neurotoxicity that arises during prion disease pathogenesis. The prion hypothesis predicts that the transmissible prion agent consists of PrP, which is comprised of aggregated misfolded conformers of the normal host protein PrP. It is important to understand the biology of transmissible prions and to identify genetic modifiers of prion-induced neurotoxicity. This information will underpin the development of therapeutic and control strategies for human and animal prion diseases. The most reliable method to detect prion infectivity is by in vivo transmission in a suitable experimental host, which to date have been mammalian species. Current prion bioassays are slow, cumbersome and relatively insensitive to low titres of prion infectivity, and do not lend themselves to rapid genetic analysis of prion disease. Here, we provide an overview of our novel studies that have led to the establishment of Drosophila melanogaster, a genetically well-defined invertebrate host, as a sensitive, versatile and economically viable animal model for the detection of mammalian prion infectivity and genetic modifiers of prion-induced toxicity.
Topics: Animals; Humans; Drosophila; Drosophila melanogaster; Animals, Genetically Modified; Prion Diseases; Prions; Mammals
PubMed: 35092497
DOI: 10.1007/s00441-022-03586-0 -
Genetics in Medicine : Official Journal... Oct 2022Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant... (Review)
Review
Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype-phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.
Topics: Genetic Counseling; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions
PubMed: 35819418
DOI: 10.1016/j.gim.2022.06.003