Prion [JOURNAL]
Sun
200 papers
Insight into the conserved structural dynamics of the C-terminus of mammal PrPC identifies structural core and possible structural role of pharmacological chaperones.
Soto P, Gloeb GM, Tsuchida KA … +3 more , Charles AA, Greenwood NM, Hendrickson H
Prion · 2023 Dec · PMID 36892160 · Full text
Misfolding of the prion protein is central to prion disease aetiology. Although understanding the dynamics of the native fold helps to decipher the conformational conversion mechanism, a complete depiction of distal but...
Misfolding of the prion protein is central to prion disease aetiology. Although understanding the dynamics of the native fold helps to decipher the conformational conversion mechanism, a complete depiction of distal but coupled prion protein sites common across species is lacking. To fill this gap, we used normal mode analysis and network analysis to examine a collection of prion protein structures deposited on the protein data bank. Our study identified a core of conserved residues that sustains the connectivity across the C-terminus of the prion protein. We propose how a well-characterized pharmacological chaperone may stabilize the fold. Also, we provide insight into the effect on the native fold of initial misfolding pathways identified by others using kinetics studies.
A family with mental disorder as the first symptom finally confirmed with Gerstmann-Sträussler-Scheinker disease with P102L mutation in PRNP gene - case report.
Chen Z, Guo J, Ran N … +3 more , Zhong Y, Yang F, Sun H
Prion · 2023 Dec · PMID 36847171 · Full text
Gerstmann-Sträussler-Scheinker (GSS) disease is an autosomal dominant neurodegenerative disease, and it is characterized by progressive cerebellar ataxia. Up to now, GSS cases with the p.P102L mutation have mainly been r...
Gerstmann-Sträussler-Scheinker (GSS) disease is an autosomal dominant neurodegenerative disease, and it is characterized by progressive cerebellar ataxia. Up to now, GSS cases with the p.P102L mutation have mainly been reported in Caucasian, but rarely in Asian populations. A 54-year-old female patient presented with an unstable gait in the hospital. Last year, she was unable to walk steadily and occasionally choked, could not even walk independently gradually. After taking her medical history, we found that she was misdiagnosed with schizophrenia before the gait problems. The patient's father showed similar symptoms and was diagnosed with brain atrophy at the age of 56, but her daughter showed no similar symptoms at present. On arrival at the Neurology Department, the patient's vital signs and laboratory examinations showed no abnormality. As the proband presented with cerebellar ataxia and had an obvious family history, we were sure that she had hereditary cerebellar ataxia. Then, patient's brain MRI showed an abnormal signal in the right parietal cortex and bilateral small ischaemic lesions in the frontal lobe. A gene panel (including 142 ataxia-related genes) was performed, and a heterozygous mutation PRNP Exon2 c.305C>T p. (Pro102Leu) was identified. Her daughter had the same heterozygous mutation. The patient was diagnosed with GSS with mental disorders as initial symptoms. After 2 months of TCM treatment, the patient's walking instability decreased, and her emotional fluctuations were less than before. In conclusion, we have reported a rare case of GSS in Sichuan, China, and the family with mental disorder as the first symptom was finally confirmed with GSS PRNP P102L mutation.
Differential involvement of amyloidogenic evolvability in oligodendropathies; Multiple Sclerosis and Multiple System Atrophy.
Wei J, Ho G, Masliah E … +1 more , Hashimoto M
Prion · 2023 Dec · PMID 36785484 · Full text
Although multiple sclerosis (MS) and multiple system atrophy (MSA) are both characterized by impaired oligodendrocytes (OLs), the aetiological relevance remains obscure. Given inherent stressors affecting OLs, the object...
Although multiple sclerosis (MS) and multiple system atrophy (MSA) are both characterized by impaired oligodendrocytes (OLs), the aetiological relevance remains obscure. Given inherent stressors affecting OLs, the objective of the present study was to discuss the possible role of amyloidogenic evolvability (aEVO) in these conditions. Hypothetically, in aEVO, protofibrils of amyloidogenic proteins (APs), including β-synuclein and β-amyloid, might form in response to diverse stressors in parental brain. Subsequently, the AP protofibrils might be transmitted to offspring via germ cells in a prion-like fashion. By virtue of the stress information conferred by protofibrillar APs, the OLs in offspring's brain might be more resilient to forthcoming stressors, perhaps reducing MS risk. aEVO could be comparable to a gene for the inheritance of acquired characteristics. On the contrary, during ageing, MSA risk is increased through antagonistic pleiotropy. Consistently, the expression levels of APs are reduced in MS, but are increased in MSA compared to controls. Furthermore, β-synuclein, the non-amyloidogenic homologue of β-synuclein, might exert a buffering effect on aEVO, and abnormal β-synuclein could also increase MS and MSA disease activity. Collectively, a better understanding of the role of aEVO in the OL diseases might lead to novel interventions for such chronic degenerative conditions.
Prion2022-pushing the boundaries.
Zerr I
Prion · 2023 Dec · PMID 36785483 · Full text
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Canine detection of chronic wasting disease (CWD) in laboratory and field settings.
Mallikarjun A, Swartz B, Kane SA … +9 more , Gibison M, Wilson I, Collins A, Moore MB, Charendoff I, Ellis J, Murphy LA, Nichols T, Otto CM
Prion · 2023 Dec · PMID 36740856 · Full text
Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy that affects both free-ranging and farmed cervid species, including mule deer, white-tailed deer, and elk (, and ). Due to the long incubat...
Chronic wasting disease (CWD) is a fatal transmissible spongiform encephalopathy that affects both free-ranging and farmed cervid species, including mule deer, white-tailed deer, and elk (, and ). Due to the long incubation period and variability of clinical signs, CWD can expand and spread to new areas before they reach diagnostically detectable levels. Antemortem testing methods currently available can be difficult to obtain and to be applied to the large numbers required for adequate surveillance. However, key volatile biomarkers could be harnessed for non-invasive antemortem surveillance. Detection dogs are the most effective tool currently available for volatile detection; dogs can effectively complete wildlife surveys at rates surpassing that of humans. This study is the first to demonstrate that trained detection dogs can be used as an antemortem test for CWD. First, we trained three dogs to differentiate between CWD-positive and CWD-negative white-tailed deer faeces in a laboratory setting. Dogs spent significantly more time at the positive sample than the negative samples, suggesting that they differentiated between the positive and negative volatile signatures. We then trained the same dogs to search for CWD-positive faecal samples in a more naturalistic field setting. In the field, dogs found 8/11 CWD-positive samples and had an average false detection rate of 13%. These results suggest that dogs can be trained to differentiate CWD-positive faeces from CWD-negative faeces in both laboratory and field settings. Future studies will compare canine accuracy to other antemortem methods, as well as improved canine training methods.
Sheep scrapie and deer rabies in England prior to 1800.
Ness A, Aiken J, McKenzie D
Prion · 2023 Dec · PMID 36654484 · Full text
Eighteenth-century England witnessed the emergence of two neurological diseases in animals. Scrapie, a transmissible spongiform encephalopathy, is a fatal neurodegenerative disease of sheep and goats that appears in clas...
Eighteenth-century England witnessed the emergence of two neurological diseases in animals. Scrapie, a transmissible spongiform encephalopathy, is a fatal neurodegenerative disease of sheep and goats that appears in classical and atypical forms. Reports of classical scrapie in continental Europe with described symptoms date back to 1750 in what is now western Poland. However, two major outbreaks of scrapie appeared in England prior to the 1800s. References to a sheep disease with a resemblance to scrapie first appear in Southwestern England between 1693 and 1722 and in the East Midlands between 1693 and 1706. Concurrent with the descriptions of scrapie in sheep was a neurological disease of deer first appearing in the East of England. Two 18th-century writers remarked on the symptomatic similarities between the sheep and deer neurological diseases. Multiple outbreaks of the unknown deer disease existing as early as 1772 are examined and are identified as rabies.
Copper coordination modulates prion conversion and infectivity in mammalian prion proteins.
Legname G
Prion · 2023 Dec · PMID 36597284 · Full text
In mammals the cellular form of the prion protein (PrP) is a ubiquitous protein involved in many relevant functions in the central nervous system. In addition to its physiological functions PrP plays a central role in a...
In mammals the cellular form of the prion protein (PrP) is a ubiquitous protein involved in many relevant functions in the central nervous system. In addition to its physiological functions PrP plays a central role in a group of invariably fatal neurodegenerative disorders collectively called prion diseases. In fact, the protein is a substrate in a process in which it converts into an infectious and pathological form denoted as prion. The protein has a unique primary structure where the unstructured N-terminal moiety possesses characteristic sequences wherein histidines are able to coordinate metal ions, in particular copper ions. These sequences are called octarepeats for their characteristic length. Moreover, a non-octarepeat fifth-copper binding site is present where copper coordination seems to control infectivity. In this review, I will argue that these sequences may play a significant role in modulating prion conversion and replication.
Prion therapeutics: Lessons from the past.
Shim KH, Sharma N, An SSA
Prion · 2022 Dec · PMID 36515657 · Full text
Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (Pr...
Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP) into scrapie isoform (PrP) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP to PrP conversion, increasing PrP removal, and PrP stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity , only a few were effective and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.
Variability in prion protein genotypes by spatial unit to inform susceptibility to chronic wasting disease.
Fameli AF, Edson J, Banfield JE … +2 more , Rosenberry CS, Walter WD
Prion · 2022 Dec · PMID 36104983 · Full text
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 v...
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 () 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 (-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.
18F-FP-CIT PET/CT in a case of probable sporadic Creutzfeldt-Jakob disease with parkinsonism as initial symptom.
Tang S, Dou X, Zhang Y
Prion · 2022 Dec · PMID 35801711 · Full text
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...
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.
Transcriptomic analysis identifies novel potential biomarkers and highlights cilium-related biological processes in the early stages of prion disease in mice.
Kim YC, Jeong BH
Prion · 2022 Dec · PMID 35786398 · Full text
Prion diseases are fatal and irreversible neurodegenerative diseases induced by the pathogenic form of the prion protein (PrP), which is converted from the benign form of the prion protein (PrP). These diseases are chara...
Prion diseases are fatal and irreversible neurodegenerative diseases induced by the pathogenic form of the prion protein (PrP), which is converted from the benign form of the prion protein (PrP). These diseases are characterized by an extended asymptomatic incubation period accompanied by continuous conversion of PrP to PrP. However, to date, the mechanism governing the conversion to PrP in the initial stages of prion disease has not been fully elucidated. We collected transcriptome data from the hippocampus of wild-type mice and prion-infected mice at 8 weeks post injection from the Gene Expression Omnibus and analysed differentially expressed genes and related signalling biological process using bioinformatic tools. We identified a total of 36 differentially expressed genes, including 22 upregulated genes and 14 downregulated genes. In addition, we identified that the cilium-related biological process was enriched in the early stages of prion disease. Furthermore, up- and down-regulated genes were associated with cilium-related cellular components and synapse-related cellular components, respectively. To the best of our knowledge, our study was the first to observe the upregulation of cilium-related genes in the early stages of prion disease.
Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report.
Bernardini A, Gigli GL, Janes F … +4 more , Pellitteri G, Ciardi C, Fabris M, Valente M
Prion · 2022 Dec · PMID 35786166 · Full text
Creutzfeldt-Jakob disease (CJD) is a rare, fatal disease presenting with rapidly progressive neurological deficits caused by the accumulation of a misfolded form (PrPSc) of prion protein (PrPc). Coronavirus disease 2019...
Creutzfeldt-Jakob disease (CJD) is a rare, fatal disease presenting with rapidly progressive neurological deficits caused by the accumulation of a misfolded form (PrPSc) of prion protein (PrPc). Coronavirus disease 2019 (COVID-19) is a primarily respiratory syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); many diverse neurological complications have been observed after COVID-19. We describe a young patient developing CJD two months after mild COVID-19. Presenting symptoms were visuospatial deficits and ataxia, evolving into a bedridden state with preserved consciousness and diffuse myoclonus. Diagnostic work-up was suggestive of CJD. The early age of onset and the short interval between respiratory and neurological symptoms might suggest a causal relationship: a COVID-19-related neuroinflammatory state may have induced the misfolding and subsequent aggregation of PrPSc. The present case emphasizes the link between neuroinflammation and protein misfolding. Further studies are needed to establish the role of SARS-CoV-2 as an initiator of neurodegeneration.
Preventive pharmacological treatment in subjects at risk for fatal familial insomnia: science and public engagement.
Forloni G, Roiter I, Artuso V … +13 more , Marcon M, Colesso W, Luban E, Lucca U, Tettamanti M, Pupillo E, Redaelli V, Mariuzzo F, Boscolo Buleghin G, Mariuzzo A, Tagliavini F, Chiesa R, Ambrosini A
Prion · 2022 Dec · PMID 35737759 · Full text
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...
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.
Difference of geographic distributions of the Chinese patients with prion diseases in the permanent resident places and referring places.
Xiao K, Pang MF, Zhao YQ … +5 more , Gao LP, Wu YZ, Wang Y, Shi Q, Dong XP
Prion · 2022 Dec · PMID 35638100 · Full text
Human prion diseases (PrDs) are a group of transmissible neurodegenerative diseases that can be clarified as sporadic, genetic and iatrogenic forms. In this study, we have analysed the time and geographic distributions o...
Human prion diseases (PrDs) are a group of transmissible neurodegenerative diseases that can be clarified as sporadic, genetic and iatrogenic forms. In this study, we have analysed the time and geographic distributions of 2011 PrD cases diagnosed by China National Surveillance for Creutzfeldt-Jakob disease (CNS-CJD) since 2006, including 1792 sporadic CJD (sCJD) cases and 219 gPrD cases. Apparently, the cases numbers of both sCJD and gPrD increased along with the surveillance years, showing a stepping up every five years. The geographic distributions of the PrDs cases based on the permanent residences were wide, distributing in 30 out of 31 provincial-level administrative divisions in Chinese mainland. However, the case numbers in the provincial level varied largely. The provinces in the eastern part of China had much more cases than those in the western part. Normalized the case numbers with the total population each province revealed higher incidences in six provinces. Further, the resident and referring places of all PrD cases were analysed, illustrating a clear concentrating pattern of referring in the large metropolises. Five provincial-level administrative divisions reported more PrD cases from other provinces than the local ones. Particularly, BJ reported not only more than one-fourth of all PrDs cases in Chinese mainland but also 3.64-fold more PrDs cases from other provinces than its local ones. We believed that good medical resources, well-trained programmes and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities.
Cellular prion protein distribution in the vomeronasal organ, parotid, and scent glands of white-tailed deer and mule deer.
Ness A, Jacob A, Saboraki K … +8 more , Otero A, Gushue D, Martinez Moreno D, de Peña M, Tang X, Aiken J, Lingle S, McKenzie D
Prion · 2022 Dec · PMID 35634740 · Full text
Chronic wasting disease (CWD) is a contagious and fatal transmissible spongiform encephalopathy affecting species of the cervidae family. CWD has an expanding geographic range and complex, poorly understood transmission...
Chronic wasting disease (CWD) is a contagious and fatal transmissible spongiform encephalopathy affecting species of the cervidae family. CWD has an expanding geographic range and complex, poorly understood transmission mechanics. CWD is disproportionately prevalent in wild male mule deer and male white-tailed deer. Sex and species influences on CWD prevalence have been hypothesized to be related to animal behaviours that involve deer facial and body exocrine glands. Understanding CWD transmission potential requires a foundational knowledge of the cellular prion protein (PrP) in glands associated with cervid behaviours. In this study, we characterized the presence and distribution of PrP in six integumentary and two non-integumentary tissues of hunter-harvested mule deer () and white-tailed deer (). We report that white-tailed deer expressed significantly more PrP than their mule deer in the parotid, metatarsal, and interdigital glands. Females expressed more PrP than males in the forehead and preorbital glands. The distribution of PrP within the integumentary exocrine glands of the face and legs were localized to glandular cells, hair follicles, epidermis, and immune cell infiltrates. All tissues examined expressed sufficient quantities of PrP to serve as possible sites of prion initial infection, propagation, and shedding.
Developing neuropalliative care for sporadic Creutzfeldt-Jakob Disease.
Harrison KL, Garrett SB, Gilissen J … +4 more , Terranova MJ, Bernstein Sideman A, Ritchie CS, Geschwind MD
Prion · 2022 Dec · PMID 35239456 · Full text
We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identifie...
We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identified caregivers of decedents with sporadic Creutzfeldt-Jakob disease from the University of California San Francisco Rapidly Progressive Dementia research database. We purposively recruited 12 caregivers for in-depth interviews and extracted associated patient data. We analysed interviews using the constant comparison method and chart data using descriptive statistics. Patients had a median age of 70 (range: 60-86) years and disease duration of 14.5 months (range 4-41 months). Caregivers were interviewed a median of 22 (range 11-39) months after patient death and had a median age of 59 (range 45-73) years. Three major sources of distress included (1) the unique nature of sporadic Creutzfeldt-Jakob disease; (2) clinical care issues such as difficult diagnostic process, lack of expertise in sporadic Creutzfeldt-Jakob disease, gaps in clinical systems, and difficulties with end-of-life care; and (3) caregiving issues, including escalating responsibilities, intensifying stress, declining caregiver well-being, and care needs surpassing resources. Two sources of support were (1) clinical care, including guidance from providers about what to expect and supportive relationships; and (2) caregiving supports, including connection to persons with experience managing Creutzfeldt-Jakob disease, instrumental support, and social/emotional support. The challenges and supports described by caregivers align with neuropalliative approaches and can be used to develop interventions to address needs of persons with sporadic Creutzfeldt-Jakob disease and their caregivers.
Penetrance of the V203I variant of the PRNP gene: report of a patient with stroke-like onset of Creutzfeld-Jacob Disease and review of published cases.
Gandoglia I, Strada L, Poleggi A … +3 more , Castaldi A, Del Sette M, Di Maria E
Prion · 2022 Dec · PMID 35167423 · Full text
Creutzfeldt-Jakob disease (CJD) is usually sporadic, but 10-15% of cases are caused by autosomal-dominant pathogenic variants in the prion protein gene (). A few variants show low penetrance. We report the case of a 64-...
Creutzfeldt-Jakob disease (CJD) is usually sporadic, but 10-15% of cases are caused by autosomal-dominant pathogenic variants in the prion protein gene (). A few 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.
Creutzfeldt-Jakob disease associated with a T188K homozygous mutation in the prion protein gene: a case report and review of the literature.
Shan Y, Zhang J, Cen Y … +4 more , Xu X, Tan R, Zhao J, Yu S
Prion · 2022 Dec · PMID 35130121 · Full text
Genetic Creutzfeldt-Jakob disease (gCJD) is a prion disease caused by mutations in the prion protein gene (). It has an autosomal dominant inheritance, so gCJD with homozygous mutations is extremely rare, and the influen...
Genetic Creutzfeldt-Jakob disease (gCJD) is a prion disease caused by mutations in the prion protein gene (). It has an autosomal dominant inheritance, so gCJD with homozygous mutations is extremely rare, and the influence of homozygous mutations on the gCJD phenotype is unknown. We describe the clinical and laboratory features of a patient with a T188K homozygous mutation and perform a literature review of gCJD cases with homozygous mutations. The patient was presented with cerebellum symptoms, cognitive decline and visual disturbances. Auxiliary examinations revealed restricted diffusion in magnetic resonance imaging and glucose hypometabolism on Fluorodeoxyglucose-positron emission tomography. No periodic sharp wave complexes were detected in electroencephalography, and the cerebrospinal fluid 14-3-3 protein was negative. sequencing revealed the presence of a homozygous T188K variant. The patient died 15 months after disease onset. A literature review revealed V203I, E200K and E200D as the only three mutations reported as homozygous in gCJD. To the best of our knowledge, this is the first report of a gCJD patient with a T188K homozygous mutation. Although the clinical manifestations of our patient were similar to those with T188K heterozygous mutations, she presented with a slightly earlier onset and had a longer survival time. This is consistent with previous observations from patients with V203I and E200K homozygous mutations. Further studies are essential to clarify the influence of homozygous mutations on the gCJD phenotype.
The first non-prion pathogen identified: neurotropic influenza virus.
Sakaguchi S, Hara H
Prion · 2022 Dec · PMID 34978525 · Full text
The cellular isoform of prion protein, designated PrP, is a membrane glycoprotein expressed most abundantly in the brain, particularly by neurons, and its conformational conversion into the abnormally folded, amyloidogen...
The cellular isoform of prion protein, designated PrP, is a membrane glycoprotein expressed most abundantly in the brain, particularly by neurons, and its conformational conversion into the abnormally folded, amyloidogenic isoform, PrP, is an underlying mechanism in the pathogenesis of prion diseases, a group of neurodegenerative disorders in humans and animals. Most cases of these diseases are sporadic and their aetiologies are unknown. We recently found that a neurotropic strain of influenza A virus (IAV/WSN) caused the conversion of PrP into PrP and the subsequent formation of infectious prions in mouse neuroblastoma cells after infection. These results show that IAV/WSN is the first non-prion pathogen capable of inducing the conversion of PrP into PrP and propagating infectious prions in cultured neuronal cells, and also provide the intriguing possibility that IAV infection in neurons might be a cause of or be associated with sporadic prion diseases. Here, we present our findings of the IAV/WSN-induced conversion of PrP into PrP and subsequent propagation of infectious prions, and also discuss the biological significance of the conversion of PrP into PrP in virus infections.
A case of V180I genetic mutation Creutzfeldt Jakob disease (CJD) with delusional misidentification as an initial symptom.
Nagata T, Shinagawa S, Kobayashi N … +2 more , Kondo K, Shigeta M
Prion · 2022 Dec · PMID 34965177 · Full text
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...
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 () 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.
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