Prion最新文献

Chronic Wasting Disease (CWD), a well-described transmissible spongiform encephalopathy of the Cervidae family, is associated with the aggregation of an abnormal isoform (PrP^CWD) of the naturally occurring host prion protein (PrP^C). Variations in the PrP gene (PRNP) have been associated with CWD rate of infection and disease progression. We analysed 568 free-ranging white-tailed deer (Odocoileus virginianus) from 9 CWD-positive Michigan counties for PRNP 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 PRNP 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.

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 PRNP 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. PRNP 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 PRNP displaying the feature of PD is rarely reported in Chinese mainland.

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.

Methionine/methionine type 1 (MM1-type) sporadic Creutzfeldt-Jakob disease (sCJD), known as the 'classic type,' shows typical clinicopathological sCJD findings. In general, patients reach an akinetic mutism state within a few months of disease onset and die soon after if supportive therapies are not administered. Here, we describe remarkable neuropathologic observations of MM1-type sCJD in a 48-year-old, Japanese man with an unusually prolonged akinetic mutism state. In the early disease stages, the patient exhibited abnormal behaviour with gait disturbance and rapidly progressive cognitive dysfunction. Diffusion-weighted magnetic resonance imaging revealed extensive cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed no mutations, and the polymorphic codon 129 exhibited methionine homozygosity. Although the patient remained stable with tube feeding for more than 2 years after reaching the akinetic mutism state, he died because of central respiratory failure 30 months after disease onset. Neuropathologic investigation showed extensive devastating lesions, such as status spongiosus, and typical spongiform changes could no longer be observed in the cerebral neocortex. Conspicuous pyramidal tract degeneration was observed. However, the regions commonly preserved in MM1-type sCJD pathology were still relatively preserved. Immunostaining revealed extensive diffuse synaptic-type PrP deposition in the grey matter. The pathological findings suggested that sCJD is a neurodegenerative disease that shows system degeneration; there are primary and secondary degenerative regions and distinct preserved regions, even in cases with prolonged disease duration. In addition, it is considered that there is a limited survival period for MM1-type sCJD, even if active symptomatic treatment is provided.

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.

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^Sc) in products of gestation. A 35-year-old woman with sCJD presented in her 10^th 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^Sc is extremely low.

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.

Cellular Prion Protein (PrP^C) is a well-studied protein as the substrate for various progressive untreatable neurodegenerative diseases. Normal functions of PrP^C are poorly understood, though recent proteomic and transcriptomic approaches have begun to reveal common themes. We use our compound prp1 and prp2 knockout mutant zebrafish at three days post fertilization to take a transcriptomic approach to investigating potentially conserved PrP^C 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^C we found that in addition to the protocadherins there was a significant reduction in transcript abundance of both ncam1a and st8sia2. 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 prp1/prp2 mutant fish or after prp1 morpholino knockdown. Our data supports a cross species conserved role for PrP^C in the development and maintenance of the central nervous system, particularly by regulating various and important cell adhesion processes.

Axis deer (Axis axis) 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 (PRNP) from axis deer. We then compared axis deer PrP^C sequences and amino acid polymorphisms to those of CWD susceptible species. A single PRNP allele with no evidence of intraspecies variation was identified in axis deer that indicates axis deer PRNP is most similar to North American elk (Cervus canadensis) PRNP. 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.

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.