scholarly journals Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein

2003 ◽  
Vol 77 (13) ◽  
pp. 7611-7622 ◽  
Author(s):  
Roberto Chiesa ◽  
Pedro Piccardo ◽  
Elena Quaglio ◽  
Bettina Drisaldi ◽  
San Ling Si-Hoe ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neuronal Apoptosis ◽  
Neurodegenerative Disorder ◽  
Intracerebral Inoculation ◽  
Resistant Form ◽  
Infectious Form ◽  
The Brain ◽  
Transmit Disease ◽  
Insight Into

ABSTRACT Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14spon). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14spon, although pathogenic, is distinct from PrPSc, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14RML, a PrPSc form of the mutant protein that is infectious and highly protease resistant. Like PrPSc, both PG14spon and PG14RML display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14RML aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.

scholarly journals Large-scale lipidomic profiling identifies novel potential biomarkers for prion diseases and highlights lipid raft-related pathways

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Yong-Chan Kim ◽  
Junbeom Lee ◽  
Dae-Weon Lee ◽  
Byung-Hoon Jeong
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Large Scale ◽  
Right Hemisphere ◽  
Prion Diseases ◽  
Lipid Extraction ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathway Enrichment Analysis ◽  
The Brain ◽  
Potential Biomarkers

AbstractPrion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.

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

eLife ◽  
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).

scholarly journals Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints

2020 ◽  
Vol 48 (19) ◽  
pp. 10615-10631 ◽  
Author(s):  
Eric Vallabh Minikel ◽  
Hien T Zhao ◽  
Jason Le ◽  
Jill O’Moore ◽  
Rose Pitstick ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Onset ◽  
Therapeutic Benefit ◽  
Dosing Regimen ◽  
Prion Strain ◽  
Disease Modifying Therapy ◽  
Prion Strains ◽  
Disease Stages ◽  
The Brain

Abstract Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

scholarly journals Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

2020 ◽  
Author(s):  
Eric Vallabh Minikel ◽  
Hien T Zhao ◽  
Jason Le ◽  
Jill O’Moore ◽  
Rose Pitstick ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Onset ◽  
Therapeutic Benefit ◽  
Dosing Regimen ◽  
Prion Strain ◽  
Disease Modifying Therapy ◽  
Prion Strains ◽  
Disease Stages ◽  
The Brain

AbstractLowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

scholarly journals Ethanolamine Is a New Anti-Prion Compound

2021 ◽  
Vol 22 (21) ◽  
pp. 11742
Author(s):  
Keiji Uchiyama ◽  
Hideyuki Hara ◽  
Junji Chida ◽  
Agriani Dini Pasiana ◽  
Morikazu Imamura ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oral Administration ◽  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Mouse Neuroblastoma ◽  
Conformational Conversion ◽  
The Brain ◽  
Cells Cultured

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrPSc levels in N2aC24L1-3 cells, but not PrPC levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.

scholarly journals A Transmembrane Form of the Prion Protein Contains an Uncleaved Signal Peptide and Is Retained in the Endoplasmic Reticululm

2001 ◽  
Vol 12 (4) ◽  
pp. 881-889 ◽  
Author(s):  
Richard S. Stewart ◽  
Bettina Drisaldi ◽  
David A. Harris
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Prion Protein ◽  
Signal Peptide ◽  
Mutant Form ◽  
Considerable Evidence ◽  
Cellular Pathways ◽  
Glycolipid Anchor ◽  
Infectious Form ◽  
Insight Into

Although there is considerable evidence that PrPScis the infectious form of the prion protein, it has recently been proposed that a transmembrane variant calledCtmPrP is the direct cause of prion-associated neurodegeneration. We report here, using a mutant form of PrP that is synthesized exclusively with theCtmPrP topology, thatCtmPrP is retained in the endoplasmic reticulum and is degraded by the proteasome. We also demonstrate thatCtmPrP contains an uncleaved, N-terminal signal peptide as well as a C-terminal glycolipid anchor. These results provide insight into general mechanisms that control the topology of membrane proteins during their synthesis in the endoplasmic reticulum, and they also suggest possible cellular pathways by whichCtmPrP may cause disease.

scholarly journals Clinical Laboratory Tests Used To Aid in Diagnosis of Human Prion Disease

2019 ◽  
Vol 57 (10) ◽  
Author(s):  
Allyson Connor ◽  
Han Wang ◽  
Brian S. Appleby ◽  
Daniel D. Rhoads
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Laboratory Testing ◽  
Clinical Laboratory ◽  
Prion Diseases ◽  
Neuron Specific Enolase ◽  
Brain Biopsy ◽  
Alpha Synuclein ◽  
Clinical Laboratory Testing ◽  
The Brain

ABSTRACT Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains the gold-standard diagnostic tool, antemortem laboratory testing can be performed to aid in the diagnosis of prion disease. This review is meant to help laboratory directors and physicians in their interpretation of test results. Laboratory assays to detect both nonspecific biomarkers of prion disease and prion-specific biomarkers can be used. The levels of nonspecific biomarkers in cerebrospinal fluid (CSF) are elevated when rapid neurodegeneration is occurring in the patient, and these markers include 14-3-3, tau, neuron-specific enolase, S100B, and alpha-synuclein. These markers have various sensitivities and specificities but are overall limited, as the levels of any of these analytes can be elevated in nonprion disease that is causing rapid damage of brain tissue. Prion-specific assays used in clinical laboratory testing are currently limited to two options. The first option is second-generation real-time quaking-induced conversion (RT-QuIC) performed on CSF, and the second option is Western blotting of a brain biopsy specimen used to detect protease-resistant prion protein. Although both tests have exquisite specificity, RT-QuIC has a sensitivity of 92 to 97.2% in symptomatic individuals, compared to the brain biopsy Western blot sensitivity of 20 to 60%. RT-QuIC was added to the Centers for Disease Control and Prevention’s diagnostic criteria for prion disease in 2018. Other caveats of laboratory testing need to be considered, as sporadic, genetic, and acquired forms of prion disease have different clinical and laboratory presentations, and these caveats are discussed. Laboratory testing plays an important role in the diagnosis of prion disease, which is often challenging to diagnose.

scholarly journals Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Robert Faris ◽  
Roger A. Moore ◽  
Anne Ward ◽  
Dan E. Sturdevant ◽  
Suzette A. Priola
Keyword(s):  
Electron Transport ◽  
Transgenic Mice ◽  
Mitochondrial Dysfunction ◽  
Prion Protein ◽  
Prion Disease ◽  
Mitochondrial Respiration ◽  
Brain Mitochondria ◽  
Prion Strain ◽  
Prion Infection ◽  
The Brain

ABSTRACT Mitochondria are crucial to proper neuronal function and overall brain health. Mitochondrial dysfunction within the brain has been observed in many neurodegenerative diseases, including prion disease. Several markers of decreased mitochondrial activity during prion infection have been reported, yet the bioenergetic respiratory status of mitochondria from prion-infected animals is unknown. Here we show that clinically ill transgenic mice overexpressing hamster prion protein (Tg7) infected with the hamster prion strain 263K suffer from a severe deficit in mitochondrial oxygen consumption in response to the respiratory complex II substrate succinate. Characterization of the mitochondrial proteome of purified brain mitochondria from infected and uninfected Tg7 mice showed significant differences in the relative abundance of key mitochondrial electron transport proteins in 263K-infected animals relative to that in controls. Our results suggest that at clinical stages of prion infection, dysregulation of respiratory chain proteins may lead to impairment of mitochondrial respiration in the brain. IMPORTANCE Mitochondrial dysfunction is present in most major neurodegenerative diseases, and some studies have suggested that mitochondrial processes may be altered during prion disease. Here we show that hamster prion-infected transgenic mice overexpressing the hamster prion protein (Tg7 mice) suffer from mitochondrial respiratory deficits. Tg7 mice infected with the 263K hamster prion strain have little or no signs of mitochondrial dysfunction at the disease midpoint but suffer from a severe deficit in mitochondrial respiration at the clinical phase of disease. A proteomic analysis of the isolated brain mitochondria from clinically affected animals showed that several proteins involved in electron transport, mitochondrial dynamics, and mitochondrial protein synthesis were dysregulated. These results suggest that mitochondrial dysfunction, possibly exacerbated by prion protein overexpression, occurs at late stages during 263K prion disease and that this dysfunction may be the result of dysregulation of mitochondrial proteins.

scholarly journals Calcineurin Activation by Prion Protein Induces Neurotoxicity via Mitochondrial Reactive Oxygen Species

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Ji-Hong Moon ◽  
Jeong-Min Hong ◽  
Sang-Youel Park
Keyword(s):  
Reactive Oxygen Species ◽  
Prion Protein ◽  
Neuronal Apoptosis ◽  
Prion Diseases ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Oxygen Species ◽  
Cellular Functions ◽  
Mitochondrial Injury ◽  
The Brain

Prion diseases are caused by PrPsc accumulation in the brain, which triggers dysfunctional mitochondrial injury and reactive oxygen species (ROS) generation in neurons. Recent studies on prion diseases suggest that endoplasmic reticulum (ER) stress induced by misfolding proteins such as misfolded prion protein results in activation of calcineurin. Calcineurin is a calcium-related protein phosphatase of type 2B that exists in copious quantities in the brain and acts as a critical nodal component in the control of cellular functions. To investigate the relationship between calcineurin and intracellular ROS, we assessed the alteration of CaN and ROS induced by prion peptide (PrP) 106-126. Human prion peptide increased mitochondrial ROS by activating calcineurin, and the inhibition of calcineurin activity protected mitochondrial function and neuronal apoptosis in neuronal cells. These results suggest that calcineurin plays a pivotal role in neuronal apoptosis by mediating mitochondrial injury and ROS in prion diseases.

scholarly journals Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1794
Author(s):  
Nicholas Brennecke ◽  
Ignazio Cali ◽  
Tze Mok ◽  
Helen Speedy ◽  
Laszlo Hosszu ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Genetic Variant ◽  
Molecular Subtype ◽  
Case Series ◽  
Low Risk ◽  
Proteinase K ◽  
Jakob Disease ◽  
Insight Into

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

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