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Frontiers in Behavioral Neuroscience 2024Prion diseases, such as scrapie, entail the accumulation of disease-specific prion protein () within the brain. Toll-like receptors (TLRs) are crucial components of the...
Prion diseases, such as scrapie, entail the accumulation of disease-specific prion protein () within the brain. Toll-like receptors (TLRs) are crucial components of the pattern recognition system. They recognize pathogen-associated molecular patterns (PAMPs) and play a central role in orchestrating host innate immune responses. The expression levels of Toll-like receptors (TLRs) in the central nervous system (CNS) were not well-defined. To establish a model of prion diseases in BALB/C mice, the 22L strain was employed. The features of the 22L strain were analyzed, and the cerebellum exhibited severe pathological changes. TLR1-13 levels in the cerebellum were measured using quantitative polymerase chain reaction (qPCR) at time points of 60, 90, 120, and the final end point (145 days post-infection). During the pathogenesis, the expression levels of Toll-like receptors (TLRs) 1, 2, 7, 8, and 9 increased in a time-dependent manner. This trend mirrored the expression patterns of (the pathological isoform of the prion protein) and glial fibrillary acidic protein. Notably, at the end point, TLR1-13 levels were significantly elevated. Protein level of TLR7 and TLR9 showed increasing at the end point of the 22L-infected mice. A deeper understanding of the increased Toll-like receptors (TLRs) in prion diseases could shed light on their role in initiating immune responses at various stages during pathogenesis. This insight is particularly relevant when considering TLRs as potential therapeutic targets for prion diseases.
PubMed: 38698886
DOI: 10.3389/fnbeh.2024.1341901 -
The Veterinary Quarterly Dec 2024Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common...
Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease and transmissible spongiform encephalopathies (TSEs). Sleep and circadian rhythm disturbances are one of the most common symptoms in patients with neurodegenerative diseases. Currently, one of the main objectives in the study of TSEs is to try to establish an early diagnosis, as clinical signs do not appear until the damage to the central nervous system is very advanced, which prevents any therapeutic approach. In this paper, we provide the first description of sleep disturbance caused by classical scrapie in clinical and preclinical sheep using polysomnography compared to healthy controls. Fifteen sheep classified into three groups, clinical, preclinical and negative control, were analysed. The results show a decrease in total sleep time as the disease progresses, with significant changes between control, clinical and pre-clinical animals. The results also show an increase in sleep fragmentation in clinical animals compared to preclinical and control animals. In addition, sheep with clinical scrapie show a total loss of Rapid Eye Movement sleep (REM) and alterations in Non Rapid Eyes Movement sleep (NREM) compared to control sheep, demonstrating more shallow sleep. Although further research is needed, these results suggest that prion diseases also produce sleep disturbances in animals and that polysomnography could be a diagnostic tool of interest in clinical and preclinical cases of prion diseases.
Topics: Animals; Scrapie; Sheep; Polysomnography; Sleep Wake Disorders; Female
PubMed: 38698657
DOI: 10.1080/01652176.2024.2349674 -
Cureus Apr 2024Creutzfeldt-Jakob disease (CJD) constitutes an aggressively advancing, terminal neurodegenerative condition classified within the spectrum of transmissible spongiform...
Creutzfeldt-Jakob disease (CJD) constitutes an aggressively advancing, terminal neurodegenerative condition classified within the spectrum of transmissible spongiform encephalopathies. The difficulty in establishing a diagnosis before death arises from the condition's rarity and the resulting limited level of suspicion attributed to it. The polymorphic nature of CJD symptoms contributes to the challenge of early diagnostic recognition. Emotional and behavioral changes have been well documented, but the initial presentation of euphoria has not been documented. Here, we present the case of a female patient who was experiencing an unusual state of euphoria followed by intermittently altered mental status. She was ultimately diagnosed with sporadic CJD, discharged home on hospice, and died within six months of discharge.
PubMed: 38694643
DOI: 10.7759/cureus.57419 -
World Journal of Clinical Cases Apr 2024Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical form of dementia characterized by memory deficits and psychomotor slowing. However, HAD...
BACKGROUND
Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical form of dementia characterized by memory deficits and psychomotor slowing. However, HAD often presents with symptoms similar to those of Creutzfeldt-Jakob disease (CJD), particularly in patients with acquired immune deficiency syndrome (AIDS).
CASE SUMMARY
We report the case of a 54-year-old male who exhibited cognitive dysfunction and secondary behavioral changes following HIV infection and suspected prion exposure. The patient was diagnosed with HIV during hospitalization and his cerebrospinal fluid tested positive for 14-3-3 proteins. His electroencephalogram showed a borderline-abnormal periodic triphasic wave pattern. Contrast-enhanced magnetic resonance imaging revealed moderate encephalatrophy and demyelination. Initially, symptomatic treatment and administration of amantadine were pursued for presumed CJD, but the patient's condition continued to deteriorate. By contrast, the patient's condition improved following anti-HIV therapy. This individual is also the only patient with this prognosis to have survived over 4 years. Thus, the diagnosis was revised to HAD.
CONCLUSION
In the diagnostic process of rapidly progressive dementia, it is crucial to rule out as many potential causes as possible and to consider an autopsy to diminish diagnostic uncertainty. The 14-3-3 protein should not be regarded as the definitive marker for CJD. Comprehensive laboratory screening for infectious diseases is essential to enhance diagnostic precision, especially in AIDS patients with potential CJD. Ultimately, a trial of diagnostic treatment may be considered when additional testing is not feasible.
PubMed: 38680258
DOI: 10.12998/wjcc.v12.i12.2065 -
Prion Dec 2024Infectious prions are resistant to degradation and remain infectious in the environment for several years. Chronic wasting disease (CWD) has been detected in cervids...
Infectious prions are resistant to degradation and remain infectious in the environment for several years. Chronic wasting disease (CWD) has been detected in cervids inhabiting North America, the Nordic countries, and South Korea. CWD-prion spread is partially attributed to carcass transport and disposal. We employed a forensic approach to investigate an illegal carcass dump site connected with a CWD-positive herd. We integrated anatomic, genetic, and prion amplification methods to discover CWD-positive remains from six white-tailed deer () and, using microsatellite markers, confirmed a portion originated from the CWD-infected herd. This approach provides a foundation for future studies of carcass prion transmission risk.
Topics: Animals; Deer; Wasting Disease, Chronic; Prions; Microsatellite Repeats
PubMed: 38676289
DOI: 10.1080/19336896.2024.2343298 -
Viruses Apr 2024Inactivated influenza A virus (IAV) vaccines help reduce clinical disease in suckling piglets, although endemic infections still exist. The objective of this study was...
Inactivated influenza A virus (IAV) vaccines help reduce clinical disease in suckling piglets, although endemic infections still exist. The objective of this study was to evaluate the detection of IAV in suckling and nursery piglets from IAV-vaccinated sows from farms with endemic IAV infections. Eight nasal swab collections were obtained from 135 two-week-old suckling piglets from four farms every other week from March to September 2013. Oral fluid samples were collected from the same group of nursery piglets. IAV RNA was detected in 1.64% and 31.01% of individual nasal swabs and oral fluids, respectively. H1N2 was detected most often, with sporadic detection of H1N1 and H3N2. Whole-genome sequences of IAV isolated from suckling piglets revealed an H1 hemagglutinin (HA) from the 1B.2.2.2 clade and N2 neuraminidase (NA) from the 2002A clade. The internal gene constellation of the endemic H1N2 was TTTTPT with a pandemic lineage matrix. The HA gene had 97.59% and 97.52% nucleotide and amino acid identities, respectively, to the H1 1B.2.2.2 used in the farm-specific vaccine. A similar H1 1B.2.2.2 was detected in the downstream nursery. These data demonstrate the low frequency of IAV detection in suckling piglets and downstream nurseries from farms with endemic infections in spite of using farm-specific IAV vaccines in sows.
Topics: Animals; Swine; Swine Diseases; Orthomyxoviridae Infections; Influenza A virus; Influenza Vaccines; Phylogeny; Farms; Animals, Suckling; Vaccination; Endemic Diseases; Influenza A Virus, H1N1 Subtype; RNA, Viral; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N2 Subtype; Genome, Viral
PubMed: 38675967
DOI: 10.3390/v16040626 -
Viruses Apr 2024Located 50 miles west of Fort Collins, Colorado, Colorado State University's Mountain Campus in Pingree Park hosted the 23rd annual Rocky Mountain Virology Association...
Located 50 miles west of Fort Collins, Colorado, Colorado State University's Mountain Campus in Pingree Park hosted the 23rd annual Rocky Mountain Virology Association meeting in 2023 with 116 participants. The 3-day event at the end of September consisted of 28 talks and 43 posters that covered the topics of viral evolution and surveillance, developments in prion research, arboviruses and vector biology, host-virus interactions, and viral immunity and vaccines. This year's Randall Jay Cohrs keynote presentation covered the topic of One Health and emerging coronaviruses. This timely discussion covered the importance of global disease surveillance, international collaboration, and trans-disciplinary research teams to prevent and control future pandemics. Peak fall colors flanked the campus and glowed along the multiple mountain peaks, allowing for pristine views while discussing science and networking, or engaging in mountain activities like fly fishing and hiking. On behalf of the Rocky Mountain Virology Association, this report summarizes select presentations from the 23rd annual meeting.
Topics: Humans; Colorado; Animals; Virology; Virus Diseases; Viruses; Prions; Arboviruses; One Health
PubMed: 38675927
DOI: 10.3390/v16040586 -
Journal of Parkinson's Disease 2024Parkinson's disease (PD) is caused by the misfolding and aggregation of α-synuclein in neurons into toxic oligomers and fibrils that have prion-like properties allowing...
BACKGROUND
Parkinson's disease (PD) is caused by the misfolding and aggregation of α-synuclein in neurons into toxic oligomers and fibrils that have prion-like properties allowing them to infect healthy neurons and to be transmitted to animal models of PD by injection or oral exposure. Given α-synuclein fibrils' potential transmission on the gut-brain axis, α-synuclein may be transmitted through colonoscopy procedures.
OBJECTIVE
This study examines a possible association between colonoscopy and PD.
METHODS
Longitudinal health insurance data of 250,000 individuals aged 50+ from 2004-2019 was analyzed. Cox proportional hazard and competing risk models with death as a competing event were estimated to calculate the risk of PD. Colonoscopy was categorized as never receiving colonoscopy, colorectal cancer (CRC) screening without or with biopsy, destruction or excision (BDE), and diagnostic colonoscopy without or with BDE.
RESULTS
We identified 6,422 new cases of PD among 221,582 individuals. The Cox model revealed a significantly increased risk of PD for patients who ever had a diagnostic colonoscopy without or with BDE (HR = 1.31; 95% CI: [1.23-1.40]; HR = 1.32 [1.22-1.42]) after adjustment for age and sex. After controlling for covariates and death, persons who ever underwent CRC screening had a 40% reduced risk of PD (CRHR = 0.60 [0.54-0.67]), while persons who underwent diagnostic colonoscopy had a 20% reduced risk of PD (CRHR = 0.81 [0.75-0.88]).
CONCLUSIONS
Colonoscopy does not increase the risk of PD, after adjusting for death and covariates. Individuals who underwent only CRC screening had the lowest risk of PD, which may be a result of a more health-conscious lifestyle.
Topics: Humans; Parkinson Disease; Colonoscopy; Male; Female; Middle Aged; Aged; Early Detection of Cancer; Risk Factors; Longitudinal Studies; Colorectal Neoplasms; Proportional Hazards Models; Aged, 80 and over
PubMed: 38669559
DOI: 10.3233/JPD-240017 -
BioRxiv : the Preprint Server For... Apr 2024Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many...
Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). This has led to the idea that acetylation influences tau aggregation. Using a HEK293 cell-based aggregation assay, we tested whether acetylation-mimicking substitutions (K→Q) on five AD-associated acetyl-modified sites (AcK-311, 353, 369, 370, 375) influenced its propensity to aggregate when exposed to tau seeds derived from two clinically distinctive diseases - AD and PSP. In combination, the presence of 5K→Q sites ablated tau aggregation induced by seeds from both AD and PSP patients, indicating that acetylation within the filament core domain of tau could have an inhibitory effect on seed-mediated aggregation. We had previously identified that a phosphorylation-mimetic on Ser305 (S→E) abrogated tau aggregation by seeds from AD patients, without affecting seeding by PSP patients. Combining the S305→E to the 5K→Q acetyl-modified sites, we found that this tau could now be seeded only by PSP patients, but not by AD patients, confirming Ser305 as a critical determinant of strain-specific tau seeding. On the other hand, acetylation-nullifying substitutions (K→R or K→A) on these same Lys sites did not alter tau seeding abilities compared to the parental tau construct. Notably, the combined acetylation-nullifying Alanine substitutions on these 5 Lys sites resulted in spontaneous self-aggregation, with the filaments resembling amorphous deposits. All together, we demonstrate that cooperative acetyl-occupancy in the tau filament core influences seeded propagation of misfolded tau as well as drives self-aggregation.
PubMed: 38659970
DOI: 10.1101/2024.04.12.589253 -
The Journal of Biological Chemistry Apr 2024Liquid-liquid phase separation (LLPS) of the mammalian prion protein is mainly driven by its intrinsically disordered N-terminal domain (N-PrP). However, the specific...
Liquid-liquid phase separation (LLPS) of the mammalian prion protein is mainly driven by its intrinsically disordered N-terminal domain (N-PrP). However, the specific intermolecular interactions that promote LLPS remain largely unknown. Here, we used extensive mutagenesis and comparative analyses of evolutionarily distant PrP species to gain insight into the relationship between protein sequence and phase behavior. LLPS of mouse PrP is dependent on two polybasic motifs in N-PrP that are conserved in all tetrapods. A unique feature of mammalian N-PrP is the octarepeat domain with four histidines that mediate binding to copper ions. We now show that the octarepeat is critical for promoting LLPS and preventing the formation of PrP aggregates. Amphibian N-PrP, which contains the polybasic motifs but lacks a repeat domain and histidines, does not undergo LLPS and forms nondynamic protein assemblies indicative of aggregates. Insertion of the mouse octarepeat domain restored LLPS of amphibian N-PrP, supporting its essential role in regulating the phase transition of PrP. This activity of the octarepeat domain was neither dependent on the four highly conserved histidines nor on copper binding. Instead, the regularly spaced tryptophan residues were critical for regulating LLPS, presumably via cation-π interactions with the polybasic motifs. Our study reveals a novel role for the tryptophan residues in the octarepeat in controlling phase transition of PrP and indicates that the ability of mammalian PrP to undergo LLPS has evolved with the octarepeat in the intrinsically disordered domain but independently of the histidines.
PubMed: 38657863
DOI: 10.1016/j.jbc.2024.107310