Prion [JOURNAL]
Sun
200 papers
Detection of two dissimilar chronic wasting disease isolates in two captive Rocky Mountain elk () herds.
Nichols TA, Nicholson EM, Liu Y … +6 more , Tao W, Spraker TR, Lavelle M, Fischer J, Kong Q, VerCauteren KC
Prion · 2021 Dec · PMID 34913829 · Full text
Chronic wasting disease (CWD) continues to spread in both wild and captive cervid herds in North America and has now been identified in wild reindeer and moose in Norway, Finland and Sweden. There is limited knowledge ab...
Chronic wasting disease (CWD) continues to spread in both wild and captive cervid herds in North America and has now been identified in wild reindeer and moose in Norway, Finland and Sweden. There is limited knowledge about the variety and characteristics of isolates or strains of CWD that exist in the landscape and their implications on wild and captive cervid herds. In this study, we evaluated brain samples from two captive elk herds that had differing prevalence, history and timelines of CWD incidence. Site 1 had a 16-year history of CWD with a consistently low prevalence between 5% and 10%. Twelve of fourteen naïve animals placed on the site remained CWD negative after 5 years of residence. Site 2 herd had a nearly 40-year known history of CWD with long-term environmental accrual of prion leading to nearly 100% of naïve animals developing clinical CWD within two to 12 years. Obex samples of several elk from each site were compared for CWD prion strain deposition, genotype in prion protein gene codon 132, and conformational stability of CWD prions. CWD prions in the obex from site 2 had a lower conformational stability than those from site 1, which was independent of prnp genotype at codon 132. These findings suggest the existence of different CWD isolates between the two sites and suggest potential differential disease attack rates for different CWD strains.
The role of microglia in prion diseases and possible therapeutic targets: a literature review.
de Melo ASLF, Lima JLD, Malta MCS … +7 more , Marroquim NF, Moreira ÁR, de Almeida Ladeia I, Dos Santos Cardoso F, Gonçalves DB, Dutra BG, Dos Santos JCC
Prion · 2021 Dec · PMID 34751640 · Full text
Creutzfeldt-Jakob disease (CJD) is a rare and fatal condition that leads to progressive neurodegeneration due to gliosis, vacuolation of central nervous system tissue, and loss of neurons. Microglia play a crucial role i...
Creutzfeldt-Jakob disease (CJD) is a rare and fatal condition that leads to progressive neurodegeneration due to gliosis, vacuolation of central nervous system tissue, and loss of neurons. Microglia play a crucial role in maintaining Central Nervous System (CNS) homoeostasis, both in health and disease, through phagocytosis and cytokine production. In the context of CJD, the immunomodulatory function of microglia turns it into a cell of particular interest. Microglia would be activated by infectious prion proteins, initially acquiring a phagocytic and anti-inflammatory profile (M2), and producing cytokines such as IL-4, IL-10, and TGF-β. Therefore, microglia are seen as a key target for the development of new treatment approaches, with many emerging strategies to guide it towards a beneficial role upon neuroinflammation, by manipulating its metabolic pathways. In such a setting, many cellular targets in microglia that can be involved in phenotype modulation, such as membrane receptors, have been identified and pointed out as possible targets for further experiments and therapeutic approaches. In this article, we review the major findings about the role of microglia in CJD, including its relationship to some risk factors associated with the development of the disease. Furthermore, considering its central role in neural immunity, we explore microglial connection with other elements of the immune system and cell signalling, such as inflammasomes, the complement and purinergic systems, and the latest finding strategies to guide these cells from harmful to beneficial roles.
Prion protein polymorphisms in Michigan white-tailed deer ().
Ott-Conn CN, Blanchong JA, Larson WA
Prion · 2021 Dec · PMID 34751633 · Full text
Chronic Wasting Disease (CWD), a well-described transmissible spongiform encephalopathy of the family, is associated with the aggregation of an abnormal isoform (PrP) of the naturally occurring host prion protein (PrP)....
Chronic Wasting Disease (CWD), a well-described transmissible spongiform encephalopathy of the family, is associated with the aggregation of an abnormal isoform (PrP) of the naturally occurring host prion protein (PrP). Variations in the PrP gene () have been associated with CWD rate of infection and disease progression. We analysed 568 free-ranging white-tailed deer () from 9 CWD-positive Michigan counties for polymorphisms. Sampling included 185 CWD-positive, 332 CWD non-detected, and an additional 51 CWD non-detected paired to CWD-positives by sex, age, and harvest location. We found 12 polymorphic sites of which 5 were non-synonymous and resulted in a change in amino acid composition. Thirteen haplotypes were predicted, of which 11 have previously been described. Using logistic regression, consistent with other studies, we found haplotypes C (OR = 0.488, 95% CI = 0.321-0.730, P < 0.001) and F (OR = 0.122, 95% CI = 0.007-0.612, P < 0.05) and diplotype BC (OR = 0.340, 95% CI = 0.154-0.709, P < 0.01) were less likely to be found in deer infected with CWD. As has also been documented in other studies, the presence of a serine at amino acid 96 was less likely to be found in deer infected with CWD (P < 0.001, OR = 0.360 and 95% CI = 0.227-0.556). Identification of polymorphisms associated with reduced vulnerability to CWD in Michigan deer and their spatial distribution can help managers design surveillance programmesand identify and prioritize areas for CWD management.
Epitope-specific anti-PrP antibody toxicity: a comparative study of human and mouse prion proteins.
Adhikari UK, Tayebi M
Prion · 2021 Dec · PMID 34632945 · Full text
Despite having therapeutic potential, anti-PrP antibodies caused a major controversy due to their neurotoxic effects. For instance, treating mice with ICSM antibodies delayed prion disease onset, but both were found to b...
Despite having therapeutic potential, anti-PrP antibodies caused a major controversy due to their neurotoxic effects. For instance, treating mice with ICSM antibodies delayed prion disease onset, but both were found to be either toxic or innocuous to neurons by researchers following cross-linking PrP. In order to elucidate and understand the reasons that led to these contradictory outcomes, we conducted a comprehensive study to assess the antibody-specific toxicity. Since most therapeutic anti-PrP antibodies were generated against human truncated recombinant PrP or full-length mouse PrP, we reasoned that host specificity (human vs murine) of PrP might influence the nature of the specific epitopes recognized by these antibodies at the structural level possibly explaining the 'toxicity' discrepancies reported previously. Initially, molecular dynamics simulation and pro-motif analysis of full-length human (hu)PrP and mouse (mo)PrP 3D structure displayed conspicuous structural differences between huPrP and moPrP. We identified 10 huPrP and 6 moPrP linear B-cell epitopes from the prion protein 3D structure where 5 out of 10 huPrP and 3 out of 6 moPrP B-cell epitopes were predicted to be potentially toxic in immunoinformatics approaches. Herein, we demonstrate that some of the predicted potentially 'toxic' epitopes identified by the analysis were similar to the epitopes recognized by the toxic antibodies such as ICSM18 (146-159), POM1 (138-147), D18 (133-157), ICSM35 (91-110), D13 (95-103) and POM3 (95-100). This study reveals the role of host specificity of PrP in epitope-specific anti-PrP antibody toxicity.
Genetic Creutzfeldt-Jakob disease shows fatal family insomnia phenotype.
Chen B, Zhang S, Xiao Y … +7 more , Wu Y, Tang W, Yan L, Zhang Z, Qin S, Dai M, You Y
Prion · 2021 Dec · PMID 34486485 · Full text
We report a case of genetic Creutzfeldt-Jakob disease (gCJD), which has a clinical phenotype that is highly similar to Fatal Family Insomnia (FFI) and has a triad of Wernicke-Korsakoff syndrome (WKs) at the developmental...
We report a case of genetic Creutzfeldt-Jakob disease (gCJD), which has a clinical phenotype that is highly similar to Fatal Family Insomnia (FFI) and has a triad of Wernicke-Korsakoff syndrome (WKs) at the developmental stage of the disease. The 51-year-old male complained of sleep disorder and imbalance who had visited five different hospitals before diagnosed. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk, and memory disturbances. The disturbances increased during the course of the disease, which led to the death of the patient 18 months after the appearance of the signs. Although the patient show negative in brain magnetic resonance imaging (MRI) and 14-3-3 protein of cerebrospinal fluid (CSF), he was finally diagnosed with gCJD disease by the human prion protein (PRNP) gene mutations.
Decoding the role of coiled-coil motifs in human prion-like proteins.
Behbahanipour M, García-Pardo J, Ventura S
Prion · 2021 Dec · PMID 34428113 · Full text
Prions are self-propagating proteins that cause fatal neurodegenerative diseases in humans. However, increasing evidence suggests that eukaryotic cells exploit prion conformational conversion for functional purposes. A r...
Prions are self-propagating proteins that cause fatal neurodegenerative diseases in humans. However, increasing evidence suggests that eukaryotic cells exploit prion conformational conversion for functional purposes. A recent study delineated a group of twenty prion-like proteins in humans, characterized by the presence of low-complexity glutamine-rich sequences with overlapping coiled-coil (CCs) motifs. This is the case of Mediator complex subunit 15 (MED15), which is overexpressed in a wide range of human cancers. Biophysical studies demonstrated that the prion-like domain (PrLD) of MED15 forms homodimers in solution, sustained by CCs interactions. Furthermore, the same coiled-coil (CC) region plays a crucial role in the PrLD structural transition to a transmissible β-sheet amyloid state. In this review, we discuss the role of CCs motifs and their contribution to amyloid transitions in human prion-like domains (PrLDs), while providing a comprehensive overview of six predicted human prion-like proteins involved in transcription, gene expression, or DNA damage response and associated with human disease, whose PrLDs contain or overlap with CCs sequences. Finally, we try to rationalize how these molecular signatures might relate to both their function and involvement in disease.
Differential astrocyte and oligodendrocyte vulnerability in murine Creutzfeldt-Jakob disease.
Andrés-Benito P, Carmona M, Douet JY … +3 more , Cassard H, Andreoletti O, Ferrer I
Prion · 2021 Dec · PMID 34225562 · Full text
Glial vulnerability to prions is assessed in murine Creutzfeldt-Jakob disease (CJD) using the tg340 mouse line expressing four-fold human PrP M129 levels on a mouse PrP null background at different days following intrace...
Glial vulnerability to prions is assessed in murine Creutzfeldt-Jakob disease (CJD) using the tg340 mouse line expressing four-fold human PrP M129 levels on a mouse PrP null background at different days following intracerebral inoculation of sCJD MM1 brain tissues homogenates. The mRNA expression of several astrocyte markers, including glial fibrillary acidic protein (), aquaporin-4 (), solute carrier family 16, member 4 (), mitochondrial pyruvate carrier 1 () and solute carrier family 1, member 2 (glial high-affinity glutamate transporter, ) increases at 120 and 180 dpi. In contrast, the mRNA expression of oligodendrocyte and myelin markers oligodendrocyte transcription factor 1 (, neural/glial antigen 2 (), solute carrier family 16, member 1 (), myelin basic protein (), myelin oligodendrocyte glycoprotein () and proteolipid protein 1 () is preserved. Yet, myelin regulatory factor () mRNA is increased at 180 dpi. In the striatum, a non-significant increase in the number of GFAP-positive astrocytes and Iba1-immunoreactive microglia occurs at 160 dpi; a significant increase in the number of astrocytes and microglia, and a significant reduction in the number of Olig2-immunoreactive oligodendrocytes occur at 180 dpi. A decrease of MBP, but not PLP1, immunoreactivity is also observed in the striatal fascicles. These observations confirm the vulnerability and the reactive responses of astrocytes, together with the microgliosis at middle stages of prion diseases. More importantly, these findings show oligodendrocyte vulnerability and myelin alterations at advanced stages of murine CJD. They confirm oligodendrocyte involvement in the pathogenesis of CJD.
Upregulation of brain hepcidin in prion diseases.
Chaudhary S, Ashok A, Wise AS … +5 more , Rana NA, McDonald D, Kritikos AE, Kong Q, Singh N
Prion · 2021 Dec · PMID 34224321 · Full text
Accumulation of redox-active iron in human sporadic Creutzfeldt-Jakob disease (sCJD) brain tissue and scrapie-infected mouse brains has been demonstrated previously. Here, we explored whether upregulation of local hepcid...
Accumulation of redox-active iron in human sporadic Creutzfeldt-Jakob disease (sCJD) brain tissue and scrapie-infected mouse brains has been demonstrated previously. Here, we explored whether upregulation of local hepcidin secreted within the brain is the underlying cause of iron accumulation and associated toxicity. Using scrapie-infected mouse brains, we demonstrate transcriptional upregulation of hepcidin relative to controls. As a result, ferroportin (Fpn), the downstream effector of hepcidin and the only known iron export protein was downregulated, and ferritin, an iron storage protein was upregulated, suggesting increased intracellular iron. A similar transcriptional and translational upregulation of hepcidin, and decreased expression of Fpn and an increase in ferritin expression was observed in sCJD brain tissue. Further evaluation in human neuroblastoma cells (M17) exposed to synthetic mini-hepcidin showed downregulation of Fpn, upregulation of ferritin, and an increase in reactive oxygen species (ROS), resulting in cytotoxicity in a dose-dependent manner. Similar effects were noted in primary neurons isolated from mouse brain. As in M17 cells, primary neurons accumulated ferritin and ROS, and showed toxicity at five times lower concentration of mini-hepcidin. These observations suggest that upregulation of brain hepcidin plays a significant role in iron accumulation and associated neurotoxicity in human and animal prion disorders.
A Chinese patient with the clinical features of Parkinson's disease contains a single copy of octarepeat deletion in PRNP case report.
Shi Q, Shen XJ, Gao LP … +5 more , Xiao K, Zhou W, Wang Y, Chen C, Dong XP
Prion · 2021 Dec · PMID 34224312 · Full text
Insertion or deletion of single copy of octapeptide repeat (OR) in human PrP protein are considered as polymorphism, while of insertions of more numbers of OR and deletion of two copies of OR are associated with genetic...
Insertion or deletion of single copy of octapeptide repeat (OR) in human PrP protein are considered as polymorphism, while of insertions of more numbers of OR and deletion of two copies of OR are associated with genetic prion diseases.Here, we reported a 58-year-old female patient who displayed clinical manifestations of Parkinson's disease (PD) but contained deletion mutation of single copy of OR in one allele. The patient complained involuntary tremor of left upper limb for 18 months and her symptoms aggravation for 6 months at the time referring to Chinese National CJD surveillance system. The tremor was pronounced at rest, exacerbated by stress and disappear during sleep. Her symptoms were partially relieved after receiving medicament for PD. Neurological examination recorded involuntary movement of left hand and gear-like muscle tension of left upper limb. Coordination movement reported positive of Romberg sign and unstable in heel-keen test. EEG recorded a mild abnormality, but without periodic sharp wave complexes (PSWC). MRI showed a mild write matter demyelination. CSF protein 14-3-3 was negative. sequencing revealed heterozygosity of single copy deletion on ORs (R1-2-3-4/R1-2-2-3-4).No family history of neurodegenerative disease was recorded. Such case with a single copy of OR deletion in displaying the feature of PD is rarely reported in Chinese mainland.
PART and ARTAG tauopathies at a relatively young age as a concomitant finding in sporadic Creutzfeldt-Jakob disease.
Menšíková K, Matěj R, Parobková E … +2 more , Smětáková M, Kaňovský P
Prion · 2021 Dec · PMID 34224311 · Full text
Interactions between prion protein (PrP) and tau protein have long been discussed, especially in relation to the pathogenesis of neurodegenerative diseases. The presence of tauopathy in the genetic forms of Creutzfeldt-J...
Interactions between prion protein (PrP) and tau protein have long been discussed, especially in relation to the pathogenesis of neurodegenerative diseases. The presence of tauopathy in the genetic forms of Creutzfeldt-Jakob disease (CJD) brains is not uncommon. Molecular interactions between PrP and tau protein have been demonstrated in animal models; the role is attributed to the structural properties of misfolded isoform of the host-encoded prion protein (PrP) aggregates, especially amyloid, which contributes to the phosphorylation of tau protein, which is reflected in the frequent occurrence of tau pathology in inherited prion amyloidoses. The question is the relationship between PrP and hippocampal tau pathology without amyloid deposits (i.e. PART and ARTAG) in sporadic CJD (sCJD). The co-occurrence of these two proteinopathies in sCJD brains is quite rare. These pathological entities have been described in only a few cases of sCJD, all of them were older than 70 years. There have been speculations about the possibility of accelerating the course of pre-existing tauopathy or the possibility of accelerating the ageing process in the CJD brains. Here we present the clinical course and neuropathological findings of a patient with sCJD in whom the above mentioned tauopathies PART and ARTAG, considered to be typical for older age, were found as early as 58 years of age. According to the available information, this case represents an unusually early occurrence of age-related tauopathies not only in relation to sCJD, but also in general.
Transcriptomic analysis of zebrafish prion protein mutants supports conserved cross-species function of the cellular prion protein.
Pollock NM, Leighton P, Neil G … +1 more , Allison WT
Prion · 2021 Dec · PMID 34139950 · Full text
Cellular Prion Protein (PrP) is a well-studied protein as the substrate for various progressive untreatable neurodegenerative diseases. Normal functions of PrP are poorly understood, though recent proteomic and transcrip...
Cellular Prion Protein (PrP) is a well-studied protein as the substrate for various progressive untreatable neurodegenerative diseases. Normal functions of PrP are poorly understood, though recent proteomic and transcriptomic approaches have begun to reveal common themes. We use our compound and knockout mutant zebrafish at three days post fertilization to take a transcriptomic approach to investigating potentially conserved PrP functions during development. Gene ontology analysis shows the biological processes with the largest changes in gene expression include redox processing, transport and cell adhesion. Within these categories several different gene families were prevalent including the solute carrier proteins, cytochrome p450 enzymes and protocadherins. Continuing from previous studies identifying cell adhesion as an important function of PrP we found that in addition to the protocadherins there was a significant reduction in transcript abundance of both and . These two genes are involved in the early development of vertebrates. The alterations in cell adhesion transcripts were consistent with past findings in zebrafish and mouse prion protein mutants; however E-cadherin processing after prion protein knockdown failed to reveal any differences compared with wild type in either our double mutant fish or after morpholino knockdown. Our data supports a cross species conserved role for PrP in the development and maintenance of the central nervous system, particularly by regulating various and important cell adhesion processes.
Creutzfeldt-Jakob disease in pregnancy: the use of modified RT-QuIC to determine infectivity in placental tissues.
Luk CC, Mathiason CK, Orrù CD … +4 more , Jansen GH, Thiele A, Caughey B, Sim VL
Prion · 2021 Dec · PMID 34132175 · Full text
Sporadic Creutzfeldt-Jakob Disease (sCJD) rarely affects women of childbearing age. There is currently no evidence of vertical transmission. Given the biosafety implications of performing Caesarean sections (C-section) i...
Sporadic Creutzfeldt-Jakob Disease (sCJD) rarely affects women of childbearing age. There is currently no evidence of vertical transmission. Given the biosafety implications of performing Caesarean sections (C-section) in these patients, we used sensitive real-time quaking-induced conversion (RT-QuIC) assays to test for the infectious prion protein (PrP) in products of gestation. A 35-year-old woman with sCJD presented in her 10 gestational week with an eight month history of progressive cognitive impairment. During C-section, amniotic fluid, cord blood and placental tissue were collected and analysed using RT-QuIC protocols adapted for use with these tissues. The patient's diagnosis of sCJD, MM2 subtype, was confirmed at autopsy. There were borderline positive results in one sampled area of the placenta, but otherwise the cord blood and amniotic fluid were negative on our RT-QuIC assays. A healthy baby was delivered via C-section at 36 weeks and 3 days gestational age, with no evidence of neurological disease to date. We conclude that precautions should be taken with products of gestation, but the level of PrP is extremely low.
Human prion disease surveillance in Spain, 1993-2018: an overview.
De Pedro-Cuesta J, Almazán-Isla J, Tejedor-Romero L … +6 more , Ruiz-Tovar M, Avellanal F, Rábano A, Calero M, García López FJ, Spanish CJD Surveillance Group
Prion · 2021 Dec · PMID 34120571 · Full text
In Spain, human transmissible spongiform encephalopathies (TSEs) have been undergoing continuous surveillance for over 25 years. In 1995, the system was launched as an EU Concerted Action, with EU surveillance network pr...
In Spain, human transmissible spongiform encephalopathies (TSEs) have been undergoing continuous surveillance for over 25 years. In 1995, the system was launched as an EU Concerted Action, with EU surveillance network procedures being incorporated from 2002 onwards. The aim of this report was to describe performance and outcomes of this surveillance system across the period 1993-2018. Neurology and public health specialists from every region reported cases to a central hub at the Carlos III Health Institute, Madrid. In all, eight accidentally transmitted cases and five definite variant Creutzfeldt-Jakob disease (vCJD) patients were reported. All vCJD cases were diagnosed between 2005 and 2008. Two of these were family/dietary-related and spatially linked to a third. Yearly incidence of sporadic CJD per million was 1.25 across the period 1998-2018, and displayed a north-south gradient with the highest incidence in La Rioja, Navarre and the Basque Country. Genetic TSEs were observed to be clustered in the Basque Country, with a 4-fold incidence over the national rate. A total of 120 (5.6%) non-TSE sporadic, conformational, rapidly progressing neurodegenerative and vascular brain disorders were reported as suspect CJD. We conclude that TSEs in Spain displayed geographically uneven, stable medium incidences for the sporadic and genetic forms, a temporal and spatial family cluster for vCJD, and decreasing numbers for dura-mater-associated forms. The vCJD surveillance, framed within the EU network, might require continuing to cover all prion disorders. There is need for further strategic surveillance research focusing on case definition of rapid-course, conformational encephalopathies and surgical risk.
Long-term preservation of pharyngeal swallowing function in MM2-cortical-type sporadic Creutzfeldt-Jakob disease.
Hayashi Y, Kunieda K, Kudo T … +3 more , Kimura A, Fujishima I, Shimohata T
Prion · 2021 Dec · PMID 34078217 · Full text
Swallowing function in long-term survivors of Creutzfeldt-Jakob disease (CJD) has not been elucidated. Herein, we report a patient with MM2-cortical-type sporadic CJD (MM2C-type sCJD) with long-term preservation of phary...
Swallowing function in long-term survivors of Creutzfeldt-Jakob disease (CJD) has not been elucidated. Herein, we report a patient with MM2-cortical-type sporadic CJD (MM2C-type sCJD) with long-term preservation of pharyngeal swallowing function using videofluoroscopic (VF) examination of swallowing. A 55-year-old woman was admitted to hospital because of dyscalculia and memory disturbance 3 years after the onset of these symptoms. Neurological examination revealed dementia, extrapyramidal signs, and delusion. Diffusion-weighted MRI revealed bilateral hyperintensity in the basal ganglia and frontal, temporal, and parietal cortices. No mutation with the methionine homozygote at codon 129 was found on PRNP gene analysis. VF was performed 68 months after the onset. Although bolus transport from the oral cavity to the pharynx worsened, the pharyngeal swallowing function was preserved even 68 months after onset. Serial MRI examinations revealed no apparent atrophy of the brainstem. Single photon emission computed tomography revealed that the regional cerebral blood flow in the brainstem was preserved. These findings suggest that pseudobulbar palsy is the pathophysiology underlying dysphagia in long-term survivors of MM2C-type sCJD, probably owing to preserved brainstem function even in a state of akinetic mutism.
On the reactive states of astrocytes in prion diseases.
Baskakov IV
Prion · 2021 Dec · PMID 34057026 · Full text
Transformation of astrocytes into reactive states is considered one of the major pathological hallmarks of prion and other neurodegenerative diseases. Recent years witnessed a growing appreciation of the view that reacti...
Transformation of astrocytes into reactive states is considered one of the major pathological hallmarks of prion and other neurodegenerative diseases. Recent years witnessed a growing appreciation of the view that reactive astrocytes are intimately involved in chronic neurodegeneration; however, little is known about their role in disease pathogenesis. The current article reviews the progress of the last few years and critically discusses controversial questions of whether reactive astrocytes associated with prion diseases are neurotoxic or neuroprotective and whether bidirectional A1-A2 model is applicable for describing polarization of astrocytes. Moreover, other important topics, including reversibility of a transition to a reactive state, along with the role of microglia and other stimuli in triggering astrocyte activation are reviewed. Defining the role of reactive astrocytes in pathogenesis of neurodegenerative diseases will open unrealized opportunities for developing new therapeutic approaches against prion and other neurodegenerative diseases.
Development of molecular tools for diagnosis of Alzheimer's disease that are based on detection of amyloidogenic proteins.
Kulichikhin KY, Fedotov SA, Rubel MS … +6 more , Zalutskaya NM, Zobnina AE, Malikova OA, Neznanov NG, Chernoff YO, Rubel AA
Prion · 2021 Dec · PMID 33910450 · Full text
Alzheimer's disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically deve...
Alzheimer's disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically develops over the course of many years and is accompanied by a loss of functional autonomy, making a patient completely dependent on family members and/or healthcare workers. Critical features of AD are pathological polymerization of Aβ peptide and microtubule-associated protein tau, accompanied by alterations of their conformations and resulting in accumulation of cross-β fibrils (amyloids) in human brains. AD apparently progresses asymptomatically for years or even decades before the appearance of symptoms. Therefore, development of the early AD diagnosis at a pre-symptomatic stage is essential for potential therapies. This review is focused on current and potential molecular tools (including non-invasive methods) that are based on detection of amyloidogenic proteins and can be applicable to early diagnosis of AD.: Aβ - amyloid-β peptide; AβO - amyloid-β oligomers; AD - Alzheimer's disease; ADRDA - Alzheimer's Disease and Related Disorders Association; APH1 - anterior pharynx defective 1; APP - amyloid precursor protein; BACE1 - β-site APP-cleaving enzyme 1; BBB - brain blood barrier; CJD - Creutzfeldt-Jakob disease; CRM - certified reference material; CSF - cerebrospinal fluid; ELISA - enzyme-linked immunosorbent assay; FGD - F-fluorodesoxyglucose (2-deoxy-2-[F]fluoro-D-glucose); IP-MS - immunoprecipitation-mass spectrometry assay; MCI - mild cognitive impairment; MDS - multimer detection system; MRI - magnetic resonance imaging; NIA-AA - National Institute on Ageing and Alzheimer's Association; NINCDS - National Institute of Neurological and Communicative Disorders and Stroke; PEN2 - presenilin enhancer 2; PET - positron emission tomography; PiB - Pittsburgh Compound B; PiB-SUVR - PIB standardized uptake value ratio; PMCA - Protein Misfolding Cycling Amplification; PrP - Prion Protein; P-tau - hyperphosphorylated tau protein; RMP - reference measurement procedure; RT-QuIC - real-time quaking-induced conversion; SiMoA - single-molecule array; ThT - thioflavin T; TSEs - Transmissible Spongiform Encephslopathies; T-tau - total tau protein.
Hypothesis: AA amyloidosis is a factor causing systemic complications after coronavirus disease.
Galkin AP
Prion · 2021 Dec · PMID 33876719 · Full text
The severe course of COVID-19 causes systemic chronic inflammation and thrombosis in a wide variety of organs and tissues. The nature of these inflammations remains a mystery, although they are known to occur against the...
The severe course of COVID-19 causes systemic chronic inflammation and thrombosis in a wide variety of organs and tissues. The nature of these inflammations remains a mystery, although they are known to occur against the background of a high level of cytokine production. The high level of cytokines provokes overproduction of the Serum amyloid A (SAA) protein. Moreover, the number of studies has shown that the severe COVID-19 causes SAA overproduction. The authors of these works regard a high level of SAA exclusively as a biomarker of COVID-19. However, it should be borne in mind that overproduction of SAA can cause systemic AA amyloidosis. SAA forms cytotoxic amyloid deposits in various organs and induces inflammation and thrombosis. The consequences of COVID-19 infection are surprisingly similar to the clinical picture that is observed in AA amyloidosis. Here I present the hypothesis that AA amyloidosis is a factor causing systemic complications after coronavirus disease.
Monomeric a-synuclein (aS) inhibits amyloidogenesis of human prion protein (hPrP) by forming a stable aS-hPrP hetero-dimer.
Yamashita S, O Kamatari Y, Honda R … +4 more , Niwa A, Tomiata H, Hara A, Kuwata K
Prion · 2021 Dec · PMID 33849375 · Full text
Intermolecular interaction between hPrP and αS was investigated using high-speed atomic force microscopy, dynamic light scattering, and nuclear magnetic resonance. We found that hPrP spontaneously gathered and naturally...
Intermolecular interaction between hPrP and αS was investigated using high-speed atomic force microscopy, dynamic light scattering, and nuclear magnetic resonance. We found that hPrP spontaneously gathered and naturally formed oligomers. Upon addition of monomer αS with a disordered conformation, poly-dispersive property of hPrP was lost, and hetero-dimer formation started quite coherently, and further oligomerization was not observed. Solution structure of hPrP-αS dimer was firstly characterized using hetero-nuclear NMR spectroscopy. In this hetero-dimeric complex, C-terminal helical region of hPrP was in the molten-globule like state, while specific sites including hot spot and C-terminal region of αS selectively interacted with hPrP. Thus αS may suppress amyloidogenesis of hPrP by trapping the hPrP intermediate by the formation of a stable hetero-dimer with hPrP. hPrP, human prion protein of amino acid residues of 23-231; PrP, cellular form of prion protein; PrP, scrapie form of prion protein, HS-AFM; high speed atomic force microscopy; αS, α-synuclein; DLS, dynamic light scattering.
Characterization of the prion protein gene in axis deer () and implications for susceptibility to chronic wasting disease.
Buchholz MJ, Wright EA, Grisham BA … +3 more , Bradley RD, Arsuffi TL, Conway WC
Prion · 2021 Dec · PMID 33834939 · Full text
Axis deer () occur both in captivity and free-ranging populations in portions of North America, but to-date, no data exist pertaining to the species' susceptibility to CWD. We sequenced the prion protein gene () from axi...
Axis deer () occur both in captivity and free-ranging populations in portions of North America, but to-date, no data exist pertaining to the species' susceptibility to CWD. We sequenced the prion protein gene () from axis deer. We then compared axis deer PrP sequences and amino acid polymorphisms to those of CWD susceptible species. A single allele with no evidence of intraspecies variation was identified in axis deer that indicates axis deer is most similar to North American elk () . Therefore, axis deer may be susceptible to CWD. We recommend proactively increasing CWD surveillance for axis deer, particularly where CWD has been detected and axis deer are sympatric with native North American CWD susceptible species.
STXBP1 forms amyloid-like aggregates in rat brain and demonstrates amyloid properties in bacterial expression system.
Chirinskaite AV, Siniukova VA, Velizhanina ME … +3 more , Sopova JV, Belashova TA, Zadorsky SP
Prion · 2021 Dec · PMID 33590815 · Full text
Amyloids are the fibrillar protein aggregates with cross-β structure. Traditionally amyloids were associated with pathology, however, nowadays more data is emerging about functional amyloids playing essential roles in ce...
Amyloids are the fibrillar protein aggregates with cross-β structure. Traditionally amyloids were associated with pathology, however, nowadays more data is emerging about functional amyloids playing essential roles in cellular processes. We conducted screening for functional amyloids in rat brain. One of the identified proteins was STXBP1 taking part in vesicular transport and neurotransmitter secretion. Using SDD-AGE and protein fractionation we found out that STXBP1 forms small detergent-insoluble aggregates in rat brain. With immunoprecipitation analysis and C-DAG system, we showed that STXBP1 forms amyloid-like fibrils. Thus, STXBP1 demonstrates amyloid properties in rat brain and in bacterial expression system.
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