Prion最新文献

An 84-year-old woman who had been diagnosed as having dementia with Lewy body (DLB) upon initial examination exhibited cognitive impairments and person delusional misidentification (DMS): she transiently claimed that her spouse was a stranger. She was re-examined at the age of 89 years; her frequency of speech and activities of daily living had both decreased, leading to verbal communication difficulties complicated by sensory aphasia, and brain diffusion-weighted (DW) magnetic resonance imaging (MRI) showed cortical hyperintensities in some areas of both hemispheres. About 4 months later, the DW high-intensity areas were observed to have expanded into diffuse cortical areas. While the clinical features of Creutzfeldt Jakob disease (CJD) (myoclonus; ataxia; parkinsonism; rapidly progressive cognitive impairments; periodic sharp discharges on electroencephalograms) were not observed, a genetic analysis of the prion protein (PRNP) gene, which was performed because of a family history of dementia, revealed a V180I mutation (heterozygosis: valine/isoleucine) suggesting genetic CJD (g-CJD). Her activity progressively decreased, reaching akinetic mutism about 11 months after the re-examination. Finally, she suffered from severe bedsores and died from aspiration pneumonia at the age of 90 years. The present report describes the first case of person DMS as an initial neuropsychiatric symptom for V180I g-CJD; the typical long-term clinical symptoms of CJD were not observed in this patient. The inclusion of person DMS as an initial clinical symptom and the presence of expansive cortical hyperintensity areas may be useful for clinicians attempting to diagnosis V180I g-CJD in patients with elusive symptoms.

Chronic wasting disease (CWD) is a fatal encephalopathy affecting North American cervids. Certain alleles in a host's prion protein gene are responsible for reduced susceptibility to CWD. We assessed for the first time variability in the prion protein gene of elk (Cervus canadensis) present in Pennsylvania, United States of America, a reintroduced population for which CWD cases have never been reported. We sequenced the prion protein gene (PRNP) of 565 elk samples collected over 7 years (2014-2020) and found two polymorphic sites (codon 21 and codon 132). The allele associated with reduced susceptibility to CWD is present in the population, and there was no evidence of deviations from Hardy-Weinberg equilibrium in any of our sampling years (p-values between 0.14 and 1), consistent with the lack of selective pressure on the PRNP. The less susceptible genotypes were found in a frequency similar to the ones reported for elk populations in the states of Wyoming and South Dakota before CWD was detected. We calculated the proportion of less susceptible genotypes in each hunt zone in Pennsylvania as a proxy for their vulnerability to the establishment of CWD, and interpolated these results to obtain a surface representing expected proportion of the less susceptible genotypes across the area. Based on this analysis, hunt zones located in the southern part of our study area have a low proportion of less susceptible genotypes, which is discouraging for elk persistence in Pennsylvania given that these hunt zones are adjacent to the deer Disease Management Area 3, where CWD has been present since 2014.

Creutzfeldt-Jakob disease (CJD) is usually sporadic, but 10-15% of cases are caused by autosomal-dominant pathogenic variants in the prion protein gene (PRNP). A few PRNP variants show low penetrance. We report the case of a 64-year-old man, admitted to the ward with acute onset of aphasia; death occurred 6 weeks later. Brain MRI, EEG pattern and brain pathology were consistent with CJD diagnosis. Genetic analysis revealed a heterozygous V203I variant. We summarized the key clinical findings in patients carrying the V203I variant who were described to date. We also discuss the hypothesis as to whether V203I is a risk factor for CJD rather than a Mendelian disease-associated variant, as well as the possible implications of such hypothesis in the clinical scenario.

Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline - an antibiotic with a known safety profile and optimal blood-brain barrier passage - which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.

Creutzfeldt-Jakob disease (CJD) is a low-prevalence, fatal neurodegenerative disease. Parkinsonism as first symptom of CJD is rare. We present a case manifesting difficulty falling asleep as unspecific prodromal symptom and parkinsonism as initial symptom. The patient received positron emission tomography/computed tomography (PET/CT) of dopamine transporter (DAT) using 18 F-FP-CIT. The DAT-scan demonstrated presynaptic dopaminergic deficit in bilateral posterior putamen, which supports the hypothesis of nigrostriatal pathway dysfunction in CJD.

Formation of higher-order supramolecular complexes has emerged as a common principle underlying activity of a number of immune and regulated cell-death signalling pathways in animals, plants and fungi. Some of these signalosomes employ functional amyloid motifs in their assembly process. The description of such systems in fungi finds its origin in earlier studies on a fungal prion termed [Het-s], originally identified as a non-Mendelian cytoplasmic infectious element. Janine Beisson has been a key contributor to such early studies. Recent work on this and related systems offers a more integrated view framing this prion in a broader picture including related signalling systems described in animals. We propose here an auto-commentary centred on three recent studies on amyloid signalling in microbes. Collectively, these studies increase our understanding of fold conservation in functional amyloids and the structural basis of seeding, highlight the relation of fungal amyloid motifs to mammalian RHIM (RIP homotypic interaction motif) and expand the concept of Nod-like receptor-based amyloid signalosomes to the prokaryote reign.

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.

Since the discovery of bovine spongiform encephalopathy (BSE), researchers have orally challenged cattle with infected brain material to study various aspects of disease pathogenesis. Unlike most other pathogens, oral BSE challenge does not always result in the expected clinical presentation and pathology. In a recent study, steers were challenged orally with BSE and all developed clinical signs and were sacrificed and tested. However, despite a similar incubation and clinical presentation, one of the steers did not have detectable PrP^Sc in its brain. Samples from this animal were analysed for genetic differences as well as for the presence of in vitro PrP^Sc seeding activity or infectivity to determine the BSE status of this animal and the potential reasons that it was different. Seeding activity was detected in the brainstem of the abnormal steer but it was approximately one million times less than that found in the normal BSE positive steers. Intra-cranial challenge of bovinized transgenic mice resulted in no transmission of disease. The abnormal steer had different genetic sequences in non-coding regions of the PRNP gene but detection of similar genotypes in Canadian BSE field cases, that showed the expected brain pathology, suggested these differences may not be the primary cause of the abnormal result. Breed composition analysis showed a higher Hereford content in the abnormal steer as well as in two Canadian atypical BSE field cases and several additional abnormal experimental animals. This study could point towards a possible impact of breed composition on BSE pathogenesis.