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 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 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 Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease

2008 ◽  
Vol 363 (1510) ◽  
pp. 3755-3763 ◽  
Author(s):  
Sebastian Brandner ◽  
Jerome Whitfield ◽  
Ken Boone ◽  
Anderson Puwa ◽  
Catherine O'Malley ◽  
...  
Keyword(s):  
Prion Protein ◽  
Human Prion Disease ◽  
Peripheral Tissues ◽  
Prion Strain ◽  
Pathological Analysis ◽  
Lymphoreticular Tissue ◽  
Jakob Disease ◽  
Strain Type ◽  
Few Data ◽  
The Brain

While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt–Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.

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).

Enzymatic detergent treatment protocol that reduces protease-resistant prion protein load and infectivity from surgical-steel monofilaments contaminated with a human-derived prion strain

2007 ◽  
Vol 88 (10) ◽  
pp. 2905-2914 ◽  
Author(s):  
Victoria A. Lawson ◽  
James D. Stewart ◽  
Colin L. Masters
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Transmission ◽  
Prion Diseases ◽  
Medical Instrument ◽  
Treatment Protocol ◽  
Infectious Agent ◽  
Surgical Instruments ◽  
Prion Strain ◽  
Jakob Disease

The unconventional nature of the infectious agent of prion diseases poses a challenge to conventional infection control methodologies. The extraneural tissue distribution of variant and sporadic Creutzfeldt–Jakob disease has increased concern regarding the risk of prion disease transmission via general surgical procedures and highlighted the need for decontamination procedures that can be incorporated into routine processing. In this study, the ability of preparations of enzymatic medical instrument cleaners to reduce the infectivity associated with a rodent-adapted strain of human prion disease, previously reported to be resistant to decontamination, was tested. Efficient degradation of the disease-associated prion protein by enzymatic cleaning preparations required high treatment temperatures (50–60 °C). Standard decontamination methods (1 M NaOH for 1 h or autoclaving at 134 °C for 18 min) reduced infectivity associated with the human-derived prion strain by less than 3 log10 LD50. In contrast, a 30 min treatment with the optimized enzymatic cleaning preparation protocols reduced infectivity by more than 3 log10 LD50 and when used in conjunction with autoclave cycles eliminated detectable levels of infectivity. The development of prion decontamination procedures that are compatible with routine cleaning and sterilization of medical and surgical instruments may reduce the risk of the transmission of prion disease in general surgery.

scholarly journals PrP glycoforms are associated in a strain-specific ratio in native PrPSc

2005 ◽  
Vol 86 (9) ◽  
pp. 2635-2644 ◽  
Author(s):  
Azadeh Khalili-Shirazi ◽  
Linda Summers ◽  
Jacqueline Linehan ◽  
Gary Mallinson ◽  
David Anstee ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Normal Brain ◽  
Western Blots ◽  
Prion Strains ◽  
Specific Manner ◽  
First Time

Prion diseases involve conversion of host-encoded cellular prion protein (PrPC) to a disease-related isoform (PrPSc). Using recombinant human β-PrP, a panel of monoclonal antibodies was produced that efficiently immunoprecipitated native PrPSc and recognized epitopes between residues 93–105, indicating for the first time that this region is exposed in both human vCJD and mouse RML prions. In contrast, monoclonal antibodies raised to human α-PrP were more efficient in immunoprecipitating PrPC than PrPSc, and some of them could also distinguish between different PrP glycoforms. Using these monoclonal antibodies, the physical association of PrP glycoforms was studied in normal brain and in the brains of humans and mice with prion disease. It was shown that while PrPC glycoforms can be selectively immunoprecipitated, the differentially glycosylated molecules of native PrPSc are closely associated and always immunoprecipitate together. Furthermore, the ratio of glycoforms comprising immunoprecipitated native PrPSc from diverse prion strains was similar to those observed on denaturing Western blots. These studies are consistent with the view that the proportion of each glycoform incorporated into PrPSc is probably controlled in a strain-specific manner and that each PrPSc particle contains a mixture of glycoforms.

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 Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype

2015 ◽  
Vol 89 (20) ◽  
pp. 10427-10441 ◽  
Author(s):  
Jenna Crowell ◽  
Andrew Hughson ◽  
Byron Caughey ◽  
Richard A. Bessen
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Protein Gene ◽  
Phenotypic Diversity ◽  
Prion Diseases ◽  
Conformational Stability ◽  
Epigenetic Mechanism ◽  
Prion Strain ◽  
Disease Phenotypes ◽  
Prion Strains

ABSTRACTPhenotypic diversity in prion diseases can be specified by prion strains in which biological traits are propagated through an epigenetic mechanism mediated by distinct PrPScconformations. We investigated the role of host-dependent factors on phenotypic diversity of chronic wasting disease (CWD) in different host species that express the same prion protein gene (Prnp). Two CWD strains that have distinct biological, biochemical, and pathological features were identified in transgenic mice that express the Syrian golden hamster (SGH)Prnp. The CKY strain of CWD had a shorter incubation period than the WST strain of CWD, but after transmission to SGH, the incubation period of CKY CWD was ∼150 days longer than WST CWD. Limited proteinase K digestion revealed strain-specific PrPScpolypeptide patterns that were maintained in both hosts, but the solubility and conformational stability of PrPScdiffered for the CWD strains in a host-dependent manner. WST CWD produced PrPScamyloid plaques in the brain of the SGH that were partially insoluble and stable at a high concentration of protein denaturant. However, in transgenic mice, PrPScfrom WST CWD did not assemble into plaques, was highly soluble, and had low conformational stability. Similar studies using the HY and DY strains of transmissible mink encephalopathy resulted in minor differences in prion biological and PrPScproperties between transgenic mice and SGH. These findings indicate that host-specific pathways that are independent ofPrnpcan alter the PrPScconformation of certain prion strains, leading to changes in the biophysical properties of PrPSc, neuropathology, and clinical prion disease.IMPORTANCEPrions are misfolded pathogenic proteins that cause neurodegeneration in humans and animals. Transmissible prion diseases exhibit a spectrum of disease phenotypes and the basis of this diversity is encoded in the structure of the pathogenic prion protein and propagated by an epigenetic mechanism. In the present study, we investigated prion diversity in two hosts species that express the same prion protein gene. While prior reports have demonstrated that prion strain properties are stable upon infection of the same host species and prion protein genotype, our findings indicate that certain prion strains can undergo dramatic changes in biological properties that are not dependent on the prion protein. Therefore, host factors independent of the prion protein can affect prion diversity. Understanding how host pathways can modify prion disease phenotypes may provide clues on how to alter prion formation and lead to treatments for prion, and other, human neurodegenerative diseases of protein misfolding.

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.

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