Evidence for preexisting prion substrain diversity in a biologically cloned prion strain DOI Creative Commons

Tess Gunnels,

Ronald A. Shikiya,

Taylor C. York

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(9), P. e1011632 - e1011632

Published: Sept. 5, 2023

Prion diseases are a group of inevitably fatal neurodegenerative disorders affecting numerous mammalian species, including Sapiens. Prions composed PrP Sc , the disease specific conformation host encoded prion protein. strains operationally defined as heritable phenotype under controlled transmission conditions. Treatment rodents with anti-prion drugs results in emergence drug-resistant and suggest that comprised dominant strain substrains. While much experimental evidence is consistent this hypothesis, direct observation substrains has not been observed. Here we show replication required for suppression substrain. Based on reasoned selective reduction may allow Using combination biochemical methods to selectively reduce drowsy (DY) from biologically-cloned DY transmissible mink encephalopathy (TME)-infected brain resulted different properties than TME. The selection did occur during formation, suggesting identified preexisted TME-infected brain. We TME biologically stable, even conditions serial passage at high titer can lead breakdown. Substrains therefore exist where does substrain common feature prions. This mechanistic implications evolution, drug resistance interspecies transmission.

Language: Английский

Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone DOI Creative Commons
Gargi Banerjee, Simon F. Farmer, Harpreet Hyare

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 29, 2024

Abstract Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic biomarker evidence supports Aβ as the root cause AD. We previously reported human transmission pathology CAA relatively young adults who had died iatrogenic Creutzfeldt–Jakob (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated both CJD prions seeds. This raised possibility that c-hGH recipients did not die from iCJD may eventually develop Here we describe developed dementia changes within phenotypic spectrum AD, suggesting like CJD, has environmentally acquired (iatrogenic) forms well late-onset sporadic early-onset inherited forms. Although AD be rare, there no suggestion can transmitted between individuals activities daily life, its recognition emphasizes need to review measures prevent accidental transmissions via other medical surgical procedures. As propagating assemblies exhibit structural diversity akin conventional prions, it possible therapeutic strategies targeting disease-related lead selection minor components development resistance.

Language: Английский

Citations

52
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Language: Английский

Citations

51
Creutzfeldt–Jakob disease and other prion diseases DOI
Inga Zerr, Anna Ladogana, Simon Mead

et al.

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 29, 2024

Language: Английский

Citations

26
Cryo-EM of prion strains from the same genotype of host identifies conformational determinants DOI Creative Commons
Forrest Hoyt, Parvez Alam,

Efrosini Artikis

et al.

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(11), P. e1010947 - e1010947

Published: Nov. 7, 2022

Prion strains in a given type of mammalian host are distinguished by differences clinical presentation, neuropathological lesions, survival time, and characteristics the infecting prion protein (PrP) assemblies. Near-atomic structures prions from two species with different PrP sequences have been determined but comparisons distinct same amino acid sequence needed to identify purely conformational determinants strain characteristics. Here we report 3.2 Å resolution cryogenic electron microscopy-based structure 22L purified brains mice engineered express only lacking glycophosphatidylinositol anchors [anchorless (a) 22L]. Comparison this near-atomic our recently aRML propagated inbred mouse reveals that these templates for growth via incorporation molecules sequence. Both a22L assembled as stacks forming parallel in-register intermolecular β-sheets intervening loops, single monomers spanning ordered fibril core. Each monomer shares an N-terminal steric zipper, three major arches, overall V-shape, details other features differ markedly. Thus, variations shared motifs within β-stack architecture provide structural basis differentiation genotype.

Language: Английский

Citations

40
Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases DOI

Weiguanliu Zhang,

Christina D. Orrù,

Aaron Foutz

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Jan. 17, 2024

Language: Английский

Citations

9
Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer DOI Creative Commons
Parvez Alam, Forrest Hoyt,

Efrosini Artikis

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Oct. 24, 2024

Chronic wasting disease (CWD) is a widely distributed prion of cervids with implications for wildlife conservation and also human livestock health. The structures infectious prions that cause CWD other natural diseases mammalian hosts have been poorly understood. Here we report 2.8 Å resolution cryogenic electron microscopy-based structure fibrils from the brain naturally infected white-tailed deer expressing most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie fibrils, our atomic model contains single stacks molecules forming parallel in-register intermolecular β-sheets intervening loops comprising major N- C-terminal lobes within fibril cross-section. However, cervid host differ markedly rodent in many features, including ~ 180° twist relative orientation lobes. This suggests mechanisms underlying apparent transmission barrier to humans should facilitate more rational approaches development vaccines therapeutics.

Language: Английский

Citations

8
Classification of amyloidosis and protein misfolding disorders in animals 2024: A review on pathology and diagnosis DOI
Susumu Iwaide, Tomoaki Murakami,

Niki Sedghi Masoud

et al.

Veterinary Pathology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 10, 2024

Amyloidosis is a group of diseases in which proteins become amyloid, an insoluble fibrillar aggregate, resulting organ dysfunction. Amyloid deposition has been reported various animal species. To diagnose and understand the pathogenesis amyloidosis, it important to identify amyloid precursor protein involved each disease. Although 42 have humans, little known about amyloidosis animals, except for few well-described proteins, including A (AA), light chain (AL), β (Aβ), islet polypeptide-derived amyloid. Recently, several types novel identified animals using immunohistochemistry mass spectrometry-based proteomic analysis. Certain species are predisposed specific suggesting genetic background its pathogenesis. Age-related also emerged due increased longevity captive animals. In addition, experimental studies shown that some amyloids may be transmissible. Accurate diagnosis understanding necessary appropriate therapeutic intervention comparative pathological studies. This review provides updated classification associated misfolding disorders central nervous system, current their Pathologic features presented together with state-of-the-art diagnostic methods can applied routine identification

Language: Английский

Citations

7
Impacts of D-aspartate on the aggregation kinetics and structural polymorphism of amyloid β peptide 1-42 DOI

Li Li Hsiao,

Chih‐Hsuan Lee, Karine Mazmanian

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169092 - 169092

Published: March 1, 2025

Language: Английский

Citations

1
The Evolution of Experimental Rodent Models for Prion Diseases DOI
Joseph DeFranco, Glenn C. Telling

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(3)

Published: March 1, 2025

ABSTRACT Prion diseases are a group of fatal, neurodegenerative that affect animals and humans. These characterized by the conformational conversion normal, host‐encoded PrP C into disease‐causing prion isoform, Sc . Significant advancements in biological, genetic, research have led to capability studying this pathogenetic process using recombinant proteins, ex vivo systems, vitro models, mammalian hosts, latter being gold standard for assaying infectivity, transmission, strain evolution. While devoid nucleic acid, prions encipher information conformation their constituent infectious with diversity altering pathogenesis, host‐range dynamics, efficacy therapeutics. To properly study properties natural develop appropriate therapeutic strategies, it is essential utilize models authentically recapitulate these agents experimental hosts. In review, we examine evolution on non‐transgenic transgenic animals, primarily focusing rodent models. We discuss successes limitations each system provide insights based recent findings novel gene‐targeted mice. image

Language: Английский

Citations

1
Convergent generation of atypical prions in knockin mouse models of genetic prion disease DOI Creative Commons
Surabhi Mehra,

Matthew E.C. Bourkas,

Lech Kaczmarczyk

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(15)

Published: July 31, 2024

Most cases of human prion disease arise due to spontaneous misfolding WT or mutant protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether generation can occur within the mouse lifespan absence protein overexpression and how disease-causing mutations affect strain properties. To address these issues, we generated knockin mice that express misfolding-prone bank vole (BVPrP). While expressing BVPrP (I109 variant) remained free from neurological disease, a subset with (D178N E200K) causing genetic developed progressive illness. Brains spontaneously ill contained disease-specific neuropathological changes as well atypical protease-resistant BVPrP. Moreover, brain extracts D178N- E200K-mutant BVPrP-knockin exhibited seeding activity transmitted Surprisingly, properties prions appeared identical before after transmission, suggesting both guide formation similar strain. These findings imply develop bona fide diseases may share uniform initial mechanism action.

Language: Английский

Citations

6