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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 Jun 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.
Topics: Animals; Copper; Histidine; Mice; Prion Proteins; Protein Domains; Amino Acid Motifs; Humans; Phase Separation
PubMed: 38657863
DOI: 10.1016/j.jbc.2024.107310 -
BMC Veterinary Research Apr 2024Chronic wasting disease (CWD) is a prion disease of captive and free-ranging cervids. Currently, a definitive diagnosis of CWD relies on immunohistochemistry detection...
BACKGROUND
Chronic wasting disease (CWD) is a prion disease of captive and free-ranging cervids. Currently, a definitive diagnosis of CWD relies on immunohistochemistry detection of PrP in the obex and retropharyngeal lymph node (RPLN) of the affected cervids. For high-throughput screening of CWD in wild cervids, RPLN samples are tested by ELISA followed by IHC confirmation of positive results. Recently, real-time quacking-induced conversion (RT-QuIC) has been used to detect CWD positivity in various types of samples. To develop a blood RT-QuIC assay suitable for CWD diagnosis, this study evaluated the assay sensitivity and specificity with and without ASR1-based preanalytical enrichment and NaI as the main ionic component in assay buffer.
RESULTS
A total of 23 platelet samples derived from CWD-positive deer (ELISA + /IHC +) and 30 platelet samples from CWD-negative (ELISA-) deer were tested. The diagnostic sensitivity was 43.48% (NaCl), 65.22% (NaI), 60.87% (NaCl-ASR1) or 82.61% (NaI-ASR1). The diagnostic specificity was 96.67% (NaCl), 100% (NaI), 100% (NaCl-ASR1), or 96.67% (NaI-ASR1). The probability of detecting CWD prion in platelet samples derived from CWD-positive deer was 0.924 (95% CRI: 0.714, 0.989) under NaI-ASR1 experimental condition and 0.530 (95% CRI: 0.156, 0.890) under NaCl alone condition. The rate of amyloid formation (RFA) was greatest under the NaI-ASR1 condition at 10 (0.01491, 95% CRI: 0.00675, 0.03384) and 10 (0.00629, 95% CRI: 0.00283, 0.01410) sample dilution levels.
CONCLUSIONS
Incorporation of ASR1-based preanalytical enrichment and NaI as the main ionic component significantly improved the sensitivity of CWD RT-QuIC on deer platelet samples. Blood test by the improved RT-QuIC assay may be used for antemortem and postmortem diagnosis of CWD.
Topics: Animals; Deer; Wasting Disease, Chronic; Sensitivity and Specificity; Blood Platelets; Enzyme-Linked Immunosorbent Assay; Prions
PubMed: 38654224
DOI: 10.1186/s12917-024-04005-y -
Cell Death & Disease Apr 2024The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species...
The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species with lipid peroxidation is ferroptosis, which shows hallmarks of both programmed and necrotic death in vitro. While evidence of ferroptosis in neurodegenerative disease is indicated by iron accumulation and involvement of lipids, a stable marker for ferroptosis has not been identified. Its prevalence is thus undetermined in human pathophysiology, impeding recognition of disease areas and clinical investigations with candidate drugs. Here, we identified ferroptosis marker antigens by analyzing surface protein dynamics and discovered a single protein, Fatty Acid-Binding Protein 5 (FABP5), which was stabilized at the cell surface and specifically elevated in ferroptotic cell death. Ectopic expression and lipidomics assays demonstrated that FABP5 drives redistribution of redox-sensitive lipids and ferroptosis sensitivity in a positive-feedback loop, indicating a role as a functional biomarker. Notably, immunodetection of FABP5 in mouse stroke penumbra and in hypoxic postmortem patients was distinctly associated with hypoxically damaged neurons. Retrospective cell death characterized here by the novel ferroptosis biomarker FABP5 thus provides first evidence for a long-hypothesized intrinsic ferroptosis in hypoxia and inaugurates a means for pathological detection of ferroptosis in tissue.
Topics: Ferroptosis; Fatty Acid-Binding Proteins; Animals; Humans; Biomarkers; Mice; Hypoxia, Brain; Mice, Inbred C57BL; Lipid Peroxidation; Male; Neoplasm Proteins
PubMed: 38653992
DOI: 10.1038/s41419-024-06681-y -
Biochimica Et Biophysica Acta.... Jun 2024Clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this, diagnosis at asymptomatic stages of Alzheimer's disease...
Clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this, diagnosis at asymptomatic stages of Alzheimer's disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is dysregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrP) during disease progression. That is why, by means of cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3'UTR of human PRNP gene, we selected miR-519a-3p for our study. Then, in vitro experiments were carried out in two ways. First, we validated miR-519a-3p target on 3'UTR-PRNP, and second, we analyzed the levels of PrP expression after using of mimic technology on cell culture. In addition, RT-qPCR was performed to analyzed miR-519a-3p expression in human cerebral samples of AD at different stages of disease evolution. Additionally, samples of other neurodegenerative diseases such as other non-AD tauopathies and several synucleinopathies were included in the study. Our results showed that miR-519a-3p overlaps with PRNP 3'UTR in vitro and promotes downregulation of PrP. Moreover, miR-519a-3p was found to be up-regulated exclusively in AD samples from stage I to VI, suggesting its potential use as a novel label of preclinical stages of the disease.
Topics: Humans; MicroRNAs; Alzheimer Disease; Prion Proteins; Biomarkers; 3' Untranslated Regions; Female; Aged; Male; Aged, 80 and over; PrPC Proteins
PubMed: 38653354
DOI: 10.1016/j.bbadis.2024.167187 -
Prion Dec 2024The history of human prion diseases began with the original description, by Hans Gerhard Creutzfeldt and by Alfons Maria Jakob, of patients with a severe brain disease...
The history of human prion diseases began with the original description, by Hans Gerhard Creutzfeldt and by Alfons Maria Jakob, of patients with a severe brain disease that included speech abnormalities, confusion, and myoclonus, in a disease that was then named Creutzfeldt Jakob disease (CJD). Later, in Papua New Guinea, a disease characterized by trembling was identified, and given the name "Kuru". Neuropathological examination of the brains from CJD and Kuru patients, and of brains of sheep with scrapie disease revealed significant similarities and suggested a possible common mode of infection that, at the time, was thought to derive from an unknown virus that caused slow infections. John Stanley Griffith hypothesized that the agent causing these diseases was "probably a protein without nucleic acid" and, in 1982, Stanley Prusiner reported the identification of a proteinaceous infectious particle (coining the term prion) that was resistant to inactivation methods that were at the time standard for nucleic acids, and identified PrP as the major protein component of the infectious agent in scrapie and in Creutzfeldt-Jakob disease, classifying this also as a prion disease. Interestingly, the prion concept had been previously expanded to yeast proteins capable of replicating their conformation, seeding their own aggregation and transmitting phenotypic information. The prion concept has been more recently expanded to refer to misfolded proteins that are capable of converting a normal form of a protein into an abnormal form. The quest to understand and treat prion diseases has united a specific research community around the topic, and regular meetings (Prion Meetings) have taken place over the years to enable discussions, train junior researchers, and inspire research in the field.
Topics: Humans; Prion Diseases; Animals; Prions; Creutzfeldt-Jakob Syndrome; Kuru
PubMed: 38651736
DOI: 10.1080/19336896.2024.2343535