-
Sleep Medicine Aug 2023Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known...
BACKGROUND
Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS.
METHODS
We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain F-FDG-PET.
RESULTS
Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed.
CONCLUSIONS
In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.
Topics: Humans; Gerstmann-Straussler-Scheinker Disease; Insomnia, Fatal Familial; Sleep; Brain; Sleep Apnea, Obstructive; Sleep Apnea Syndromes
PubMed: 37302168
DOI: 10.1016/j.sleep.2023.05.010 -
Cell and Tissue Research Apr 2023Chronic wasting disease (CWD) strains present a novel challenge to defining and mitigating this contagious prion disease of deer, elk, moose, and reindeer. Similar to... (Review)
Review
Chronic wasting disease (CWD) strains present a novel challenge to defining and mitigating this contagious prion disease of deer, elk, moose, and reindeer. Similar to strains of other prion diseases (bovine spongiform encephalopathy, sheep scrapie), CWD strains can affect biochemical and neuropathological properties of the infectious agent, and importantly interspecies transmission. To date, ten CWD strains have been characterized. The expanding range of CWD in North America and its presence in South Korea as well as Scandinavian countries will potentially result in millions of cervids infected with CWD; thus, novel strains will continue to emerge. In this review, we will summarize the characteristics of known CWD strains and describe the impact of prion protein gene polymorphisms on the generation of strains. We will also discuss the evidence that individual cervids can harbor more than one CWD strain, complicating strain analysis, and affecting selection and adaptation of strains in new hosts.
Topics: Cattle; Animals; Sheep; Wasting Disease, Chronic; Deer; Prion Proteins; Prions
PubMed: 36201049
DOI: 10.1007/s00441-022-03688-9 -
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 -
Progress in Molecular Biology and... 2020Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been... (Review)
Review
Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been supported by tests that are mostly non-specific and, sometimes, insensitive. Recent laboratory developments have led to a variety of tests that rely on a disease-specific mechanism. One test, the CSF RT-QuIC (Real-Time Quaking-Induced Conversion) test is very sensitive and specific for sporadic CJD and is now used in routine clinical practice. Other tests, based on other tissues, including blood and urine, have been developed and potentially could improve both clinical diagnostic accuracy and lead to earlier diagnosis. While there are yet no proven treatments for prion disease, any treatment to be developed will almost certainly require earlier diagnosis if therapeutic success is to be realized.
Topics: Humans; Practice Patterns, Physicians'; Prion Diseases; Prion Proteins
PubMed: 32958229
DOI: 10.1016/bs.pmbts.2020.07.006 -
Brain : a Journal of Neurology Jan 2024A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the...
A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.
Topics: Animals; Humans; Creutzfeldt-Jakob Syndrome; DNA-Binding Proteins; Mammals; Prion Diseases; Prion Proteins; Prions
PubMed: 37669322
DOI: 10.1093/brain/awad289 -
The Lancet. Neurology Apr 2020Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a... (Review)
Review
Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single prion protein (PrP) capable of converting into the sole causal disease agent, the misfolded prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in prion disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of prion disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.
Topics: Animals; Biomarkers; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions
PubMed: 32199098
DOI: 10.1016/S1474-4422(19)30403-X -
Internal Medicine Journal Jul 2021Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been...
BACKGROUND
Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been reported in Indigenous peoples of Papua New Guinea and the United States, the occurrence and phenotype of prion disease in Indigenous Australians is hitherto unreported.
AIM
To report the incidence rate and clinical phenotype of Creutzfeldt-Jakob disease (CJD) in Indigenous Australians.
METHOD
Crude sporadic CJD (sCJD) incidence rates and indirect age standardisation of all CJD were assessed to calculate the standardised mortality ratio (SMR) of the Indigenous Australian population in comparison to the all-resident Australian population, along with analysis of clinical phenotypes.
RESULTS
We report an illustrative case of an Indigenous Australian from regionally remote Western Australia dying from typical 'probable' sCJD 2 months after disease onset, with Australian National CJD Registry (ANCJDR) surveillance overall demonstrating eight Indigenous Australians dying from sCJD (five post-mortem confirmed, three classified as 'probable') with a clinical phenotype similar to non-indigenous people, including median age at death of 61 years (interquartile range IQR = 16 years) and median duration of illness of 3 months (IQR = 1.6 months). Indigenous Australians with sCJD were geographically dispersed throughout Australia. The calculated overall crude annual rate of sCJD in Indigenous Australians compared to the remainder of the Australian population was not significantly different (0-3.87/million for Indigenous Australians; 0.94-1.83/million for non-indigenous). The overall indirect age-standardised CJD mortality ratio for the indigenous population for the years 2006-2018 was 1.49 (95% CI, 0.75-2.98), also not significantly different to the all-resident Australian population.
CONCLUSION
CJD occurs in Indigenous Australians with clinical phenotype and occurrence rates similar to non-Indigenous Australians. These findings contrast with a previous report where the incidence rate of CJD in a non-Australian indigenous population was reported to be decreased.
Topics: Australia; Creutzfeldt-Jakob Syndrome; Humans; Incidence; Infant; Prion Diseases; Registries
PubMed: 32237029
DOI: 10.1111/imj.14835 -
Revue Neurologique 2019The cell-to-cell transmission of the major pathogenic proteins of Parkinson's disease and Alzheimer's disease is reminiscent of the prion protein, which is defined as a... (Review)
Review
The cell-to-cell transmission of the major pathogenic proteins of Parkinson's disease and Alzheimer's disease is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal transmissible spongiform encephalopathies. The possibility has raised that the pathogenic proteins of Parkinson's and Alzheimer's disease are infectious, i.e. that they can transmit disease from human to human. In this review, we address this question by comparing the similarities and differences between Alzheimer's disease/Parkinson's disease pathological proteins and prions and by discussing the possible consequences for disease transmission risk.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Parkinson Disease; Prion Diseases; alpha-Synuclein; tau Proteins
PubMed: 31358351
DOI: 10.1016/j.neurol.2019.07.003 -
Annual Review of Genetics Dec 2019Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including... (Review)
Review
Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene () and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of , whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.
Topics: Animals; Cattle; Disease Models, Animal; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Goats; Humans; Mammals; Mice; Polymorphism, Genetic; Prion Diseases; Prion Proteins; Selection, Genetic; Sheep
PubMed: 31537104
DOI: 10.1146/annurev-genet-120213-092352 -
Progress in Molecular Biology and... 2020Mammalian prion or PrP is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein or PrP.... (Review)
Review
Mammalian prion or PrP is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein or PrP. Sialylation of the prion protein, a terminal modification of N-linked glycans, was discovered more than 30 years ago, yet the role of sialylation in prion pathogenesis is not well understood. This chapter summarizes current knowledge on the role of sialylation of the prion protein in prion diseases. First, we discuss recent data suggesting that sialylation of PrP N-linked glycans determines the fate of prion infection in an organism and control prion lymphotropism. Second, emerging evidence pointing out at the role N-glycans in neuroinflammation are discussed. Thirds, this chapter reviews a mechanism postulating that sialylated N-linked glycans are important players in defining strain-specific structures. A new hypothesis according to which individual strain-specific PrP structures govern selection of PrP sialoglycoforms is discussed. Finally, this chapter explain how N-glycan sialylation control the prion replication and strain interference. In summary, comprehensive review of our knowledge on N-linked glycans and their sialylation provided in this chapter helps to answer important questions of prion biology that have been puzzling for years.
Topics: Animals; Humans; Inflammation; Models, Molecular; N-Acetylneuraminic Acid; Prion Diseases; Prions
PubMed: 32958238
DOI: 10.1016/bs.pmbts.2020.07.004