Genetic prion disease: D178N with 129MV disease modifying polymorphism—a clinical phenotype

BackgroundHuman prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty.CaseWe present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result.ConclusionPatients with genetic prion disease may have no known family history and normal EEG, MRI brain and CSF findings. PRNP gene testing should be considered for patients with subacute progressive neurological and autonomic dysfunction.

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PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

eLife ◽

10.7554/elife.65311 ◽

2021 ◽

Vol 10 ◽

Author(s):

Edoardo Bistaffa ◽

Alba Marín-Moreno ◽

Juan Carlos Espinosa ◽

Chiara Maria Giulia De Luca ◽

Federico Angelo Cazzaniga ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Protein Misfolding ◽

Brain Homogenate ◽

Olfactory Mucosa ◽

Fatal Familial Insomnia ◽

Prpsc Deposition ◽

Astroglial Activation ◽

The Brain ◽

D178n Mutation

Background:Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).Methods:In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.Results:All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.Conclusions:Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.Funding:This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

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Prion Disease

Seminars in Neurology ◽

10.1055/s-0039-1687841 ◽

2019 ◽

Vol 39 (04) ◽

pp. 428-439 ◽

Cited By ~ 3

Author(s):

Kelly J. Baldwin ◽

Cynthia M. Correll

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Fatal Familial Insomnia ◽

Clinical Presentations ◽

Disease Case ◽

Jakob Disease ◽

Case Discussions

AbstractPrion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups of prion diseases, termed sporadic (Creutzfeldt–Jakob disease [CJD], sporadic fatal insomnia, and variably protease-sensitive prionopathy), genetic (genetic CJD, fatal familial insomnia, and Gerstmann–Straussler–Scheinker syndrome), and acquired (kuru, variant CJD, and iatrogenic CJD). This article will review the pathophysiology, genetics, clinical presentations, and diagnostic challenges in patients with prion disease. Case discussions, images, and tables will be used to highlight important characteristics of prion disease and prion mimics.

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CREUTZFELDT-JAKOB SYNDROME OF GENETIC ORIGIN: SERIES OF CASES IN THE ARGENTINIAN PATAGONIA

Journal of Basic and Applied Genetics ◽

10.35407/bag.2020.31.01.01 ◽

2020 ◽

Vol 31 (1) ◽

pp. 7-13

Author(s):

G. Exeni Díaz ◽

M. Costa ◽

J. Salman ◽

S. Ávila

Keyword(s):

Family History ◽

Neurodegenerative Disorder ◽

Prion Diseases ◽

Neuropsychiatric Symptoms ◽

Poor Response ◽

Prnp Gene ◽

Common Mutation ◽

Psychiatric Medication ◽

Progressive Dementia ◽

Initial Symptoms

Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 per 1,000,000 in humans per year, typically characterized by rapidly progressive dementia, ataxia, myoclonus and behavioral changes. Genetic prion diseases, which develop due to a mutation in the prion protein gene (PRNP), account for an estimated 10 to 15% of all CJD cases. Familial CJD is transmitted with an autosomal dominant inheritance pattern with high penetrance. Worldwide, the most common mutation is E200K (glutamate to lysine). We report four families with CJD assisted in Neuquén Hospital in 2018. Three of the four index cases had family history of neurological and psychiatric illness, though data was not taken into consideration at the moment of evaluation of the new cases. The most significant data recorded for a genetic consultation was when the problem had started, and it was required by a neurologist. The initial symptoms were persistent insomnia and depression with poor response to habitual psychiatric medication. Impoverishment is fast with visual disorder, myoclonias, ataxia, dementia and loss of language. Pedigree analysis allowed the identification of 144persons with the gene potential, who can develop the disease at any time in their adulthood. In all cases, mutation E200K was identified. There is a region of increased frequency of CJD. There must be suspicion on patients with neuropsychiatric symptoms and suspected family history(familiar background). Finding of the mutation confirms the diagnosis in patients and allows the identification on pre-symptomatic individuals. Challenge is posed on gene advice and to avoid iatrogenic disorder transmission. Key words: Familial Creutzfeldt-Jakob Syndrome, PRNP gene, E200K, CJD in Patagonia

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Novel Polymorphisms and Genetic Features of the Prion Protein Gene (PRNP) in Cats, Hosts of Feline Spongiform Encephalopathy

Genes ◽

10.3390/genes12010013 ◽

2020 ◽

Vol 12 (1) ◽

pp. 13

Author(s):

Hyeon-Ho Kim ◽

Yong-Chan Kim ◽

Kiwon Kim ◽

An-Dang Kim ◽

Byung-Hoon Jeong

Keyword(s):

Genetic Polymorphisms ◽

Prion Protein ◽

Structural Stability ◽

Prion Disease ◽

Protein Gene ◽

Structural Characteristics ◽

Prion Diseases ◽

Prnp Gene ◽

Spongiform Encephalopathy ◽

Prion Protein Gene

Prion diseases are fatal neurodegenerative disorders characterized by vacuolation and gliosis in the brain. Prion diseases have been reported in several mammals, and genetic polymorphisms of the prion protein gene (PRNP) play an essential role in the vulnerability of prion diseases. However, to date, investigations of PRNP polymorphisms are rare in cats, which are the major host of feline spongiform encephalopathy (FSE). Thus, we investigated the genetic polymorphisms of the cat PRNP gene and analyzed the structural characteristics of the PrP of cats compared to those of dog, prion disease-resistant animal. To investigate the genetic variations of the cat PRNP gene in 208 cats, we performed amplicon sequencing and examined the genotype, allele and haplotype frequencies of cat PRNP polymorphisms. We evaluated the influence of cat PRNP polymorphisms using PolyPhen-2, PANTHER, PROVEAN and AMYCO. In addition, we carried out structural analysis of cat PrP according to the allele of nonsynonymous single nucleotide polymorphism (SNP) (c.457G > A, Glu153Lys) using Swiss-PdbViewer. Finally, we compared the structural differences between cat and canine PrPs for SNPs associated with prion disease resistance in dogs. We identified a total of 15 polymorphisms, including 14 novel SNPs and one insertion/deletion polymorphism (InDel). Among them, Glu153Lys was predicted to affect the structural stability and amyloid propensity of cat PrP. In addition, asparagine at codon 166 of cat PrP was predicted to have longer hydrogen bond than aspartic acid at codon 163 of canine PrP. Furthermore, substitution to dog-specific amino acids in cat PrP showed an increase in structural stability. To the best of our knowledge, this is the first study regarding the structural characteristics of cat PRNP gene.

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PET Imaging of Adenosine Receptors in Diseases

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190708163407 ◽

2019 ◽

Vol 19 (16) ◽

pp. 1445-1463 ◽

Cited By ~ 3

Author(s):

Jindian Li ◽

Xingfang Hong ◽

Guoquan Li ◽

Peter S. Conti ◽

Xianzhong Zhang ◽

...

Keyword(s):

Pet Imaging ◽

Adenosine Receptors ◽

Neurological Diseases ◽

G Protein Coupled Receptors ◽

Extracellular Adenosine ◽

Positron Emission ◽

Imaging Probes ◽

Pet Probes ◽

Cancer And Inflammation ◽

G Protein Coupled

Adenosine receptors (ARs) are a class of purinergic G-protein-coupled receptors (GPCRs). Extracellular adenosine is a pivotal regulation molecule that adjusts physiological function through the interaction with four ARs: A1R, A2AR, A2BR, and A3R. Alterations of ARs function and expression have been studied in neurological diseases (epilepsy, Alzheimer’s disease, and Parkinson’s disease), cardiovascular diseases, cancer, and inflammation and autoimmune diseases. A series of Positron Emission Tomography (PET) probes for imaging ARs have been developed. The PET imaging probes have provided valuable information for diagnosis and therapy of diseases related to alterations of ARs expression. This review presents a concise overview of various ARs-targeted radioligands for PET imaging in diseases. The most recent advances in PET imaging studies by using ARs-targeted probes are briefly summarized.

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Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

Molecular Neurobiology ◽

10.1007/s12035-021-02489-5 ◽

2021 ◽

Author(s):

Marina Betancor ◽

Laura Moreno-Martínez ◽

Óscar López-Pérez ◽

Alicia Otero ◽

Adelaida Hernaiz ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Prion Disease ◽

Tetanus Toxin ◽

Neuronal Survival ◽

Prion Diseases ◽

Cellular Prion Protein ◽

Murine Models ◽

Terminal Fragment ◽

Lateral Sclerosis

AbstractThe non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

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Detection of Prions in Brain Homogenates and CSF Samples Using a Second-Generation RT-QuIC Assay: A Useful Tool for Retrospective Analysis of Archived Samples

Pathogens ◽

10.3390/pathogens10060750 ◽

2021 ◽

Vol 10 (6) ◽

pp. 750

Author(s):

Tibor Moško ◽

Soňa Galušková ◽

Radoslav Matěj ◽

Magdalena Brůžová ◽

Karel Holada

Keyword(s):

Retrospective Analysis ◽

Prion Disease ◽

Second Generation ◽

Prion Diseases ◽

Neuropsychiatric Symptoms ◽

Final Diagnosis ◽

Post Mortem ◽

Long Term Storage ◽

Archived Samples

The possibilities for diagnosing prion diseases have shifted significantly over the last 10 years. The RT-QuIC assay option has been added for neuropsychiatric symptoms, supporting biomarkers and final post-mortem confirmation. Samples of brain homogenates used for final diagnosis, archived for many years, provide the possibility for retrospective studies. We used a second-generation RT-QuIC assay to detect seeding activity in different types of sporadic and genetic prion diseases in archival brain homogenates and post-mortem CSF samples that were 2 to 15 years old. Together, we tested 92 archival brain homogenates: 39 with definite prion disease, 28 with definite other neurological disease, and 25 with no signs of neurological disorders. The sensitivity and specificity of the assay were 97.4% and 100%, respectively. Differences were observed in gCJD E200K, compared to the sporadic CJD group. In 52 post-mortem CSF samples—24 with definite prion disease and 28 controls—we detected the inhibition of seeding reaction due to high protein content. Diluting the samples eliminated such inhibition and led to 95.8% sensitivity and 100% specificity of the assay. In conclusion, we proved the reliability of archived brain homogenates and post-mortem CSF samples for retrospective analysis by RT-QuIC after long-term storage, without changed reactivity.

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Deletion of Kif5c Does Not Alter Prion Disease Tempo or Spread in Mouse Brain

Viruses ◽

10.3390/v13071391 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1391

Author(s):

Brent Race ◽

Katie Williams ◽

Chase Baune ◽

James F. Striebel ◽

Clayton W. Winkler ◽

...

Keyword(s):

Prion Disease ◽

Molecular Motors ◽

Prion Diseases ◽

Mouse Strains ◽

Survival Times ◽

Knock Out ◽

Transport Vesicles ◽

The Central Nervous System ◽

Knock Out Mice ◽

Scrapie Strains

In prion diseases, the spread of infectious prions (PrPSc) is thought to occur within nerves and across synapses of the central nervous system (CNS). However, the mechanisms by which PrPSc moves within axons and across nerve synapses remain undetermined. Molecular motors, including kinesins and dyneins, transport many types of intracellular cargo. Kinesin-1C (KIF5C) has been shown to transport vesicles carrying the normal prion protein (PrPC) within axons, but whether KIF5C is involved in PrPSc axonal transport is unknown. The current study tested whether stereotactic inoculation in the striatum of KIF5C knock-out mice (Kif5c−/−) with 0.5 µL volumes of mouse-adapted scrapie strains 22 L or ME7 would result in an altered rate of prion spreading and/or disease timing. Groups of mice injected with each strain were euthanized at either pre-clinical time points or following the development of prion disease. Immunohistochemistry for PrP was performed on brain sections and PrPSc distribution and tempo of spread were compared between mouse strains. In these experiments, no differences in PrPSc spread, distribution or survival times were observed between C57BL/6 and Kif5c−/− mice.

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Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

Pharmaceuticals ◽

10.3390/ph14020095 ◽

2021 ◽

Vol 14 (2) ◽

pp. 95

Author(s):

Jacob Kosyakovsky ◽

Jared Fine ◽

William Frey ◽

Leah Hanson

Keyword(s):

Targeted Delivery ◽

Cognitive Aging ◽

Brain Aging ◽

Neurological Diseases ◽

Iron Chelation ◽

Iron Chelator ◽

Modern Medicine ◽

Potential Applicability ◽

Disease Modifying ◽

Further Development

Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.

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The First Report of the Prion Protein Gene (PRNP) Sequence in Pekin Ducks (Anas platyrhynchos domestica): The Potential Prion Disease Susceptibility in Ducks

Genes ◽

10.3390/genes12020193 ◽

2021 ◽

Vol 12 (2) ◽

pp. 193

Author(s):

Min-Ju Jeong ◽

Yong-Chan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Prion Protein ◽

Dna Sequence ◽

Prion Disease ◽

Protein Gene ◽

Prnp Gene ◽

Pekin Duck ◽

Prion Protein Gene ◽

First Report ◽

Aggregation Propensity ◽

Pekin Ducks

Pathogenic prion protein (PrPSc), converted from normal prion protein (PrPC), causes prion disease. Although prion disease has been reported in several mammalian species, chickens are known to show strong resistance to prion diseases. In addition to chickens, the domestic duck occupies a large proportion in the poultry industry and may be regarded as a potential resistant host against prion disease. However, the DNA sequence of the prion protein gene (PRNP) has not been reported in domestic ducks. Here, we performed amplicon sequencing targeting the duck PRNP gene with the genomic DNA of Pekin ducks. In addition, we aligned the PrP sequence of the Pekin duck with that of various species using ClustalW2 and carried out phylogenetic analysis using Molecular Evolutionary Genetics Analysis X (MEGA X). We also constructed the structural modeling of the tertiary and secondary structures in avian PrP using SWISS-MODEL. Last, we investigated the aggregation propensity on Pekin duck PrP using AMYCO. We first reported the DNA sequence of the PRNP gene in Pekin ducks and found that the PrP sequence of Pekin ducks is more similar to that of geese than to that of chickens and mallards (wild ducks). Interestingly, Pekin duck PrP showed a high proportion of β-sheets compared to that of chicken PrP, and a high aggregation propensity compared to that of avian PrPs. However, Pekin duck PrP with substitutions of chicken-specific amino acids showed reduced aggregation propensities. To the best of our knowledge, this is the first report on the genetic characteristics of the PRNP sequence in Pekin ducks.

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