Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice DOI Creative Commons
Mason D. Tate, H. R. Sagara Wijeratne, Byung-Wook Kim

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(11), P. 7805 - 7818

Published: Sept. 30, 2024

Abstract INTRODUCTION Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). facilitates lipidation apolipoprotein E (apoE). This study investigated whether microRNA‐33 (miR‐33)‐mediated regulation this ABCA1–APOE pathway affects phenotypes an amyloid mouse model. METHODS We generated mir‐33 +/+ ; APP/PS1 and −/− mice to determine changes pathology using biochemical histological analyses. used RNA sequencing mass spectrometry identify transcriptomic proteomic between our genotypes. also performed mechanistic experiments by determining role miR‐33 microglial migration beta (Aβ) phagocytosis. RESULTS Mir‐33 deletion increases levels reduces Aβ accumulation glial activation. Multi‐omics studies suggested regulates activation microglia. confirm that inhibition significantly DISCUSSION These results suggest might be a potential drug target modulating level, apoE lipidation, function. Highlights Loss (miR‐33) increased protein E. reduced levels, plaque deposition, gliosis. mRNAs proteins dysregulated loss relate microglia disease. Inhibition phagocytosis vitro.

Language: Английский

Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids DOI
Sjors H. W. Scheres, Benjamin Falcon, Michel Goedert

et al.

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

Citations

110
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

21
MoDAFold: a strategy for predicting the structure of missense mutant protein based on AlphaFold2 and molecular dynamics DOI Creative Commons
Lingyan Zheng, Shuiyang Shi, Xiuna Sun

et al.

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(2)

Published: Jan. 22, 2024

Abstract Protein structure prediction is a longstanding issue crucial for identifying new drug targets and providing mechanistic understanding of protein functions. To enhance the progress in this field, spectrum computational methodologies has been cultivated. AlphaFold2 exhibited exceptional precision predicting wild-type structures, with performance exceeding that other methods. However, structures missense mutant proteins using remains challenging due to intricate substantial structural alterations caused by minor sequence variations proteins. Molecular dynamics (MD) validated precisely capturing changes amino acid interactions attributed mutations. Therefore, first time, strategy entitled ‘MoDAFold’ was proposed improve accuracy reliability combining MD. Multiple case studies have confirmed superior MoDAFold compared methods, particularly AlphaFold2.

Language: Английский

Citations

19
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

39
Prion strains viewed through the lens of cryo-EM DOI Creative Commons
Szymon W. Manka,

Adam Wenborn,

John Collinge

et al.

Cell and Tissue Research, Journal Year: 2022, Volume and Issue: 392(1), P. 167 - 178

Published: Aug. 27, 2022

Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils misfolded, host-encoded prion protein (PrP) which propagate through templated polymerisation. Prion strains produce distinct clinicopathological phenotypes the same host appear to be encoded by misfolded PrP conformations assembly states. Despite fundamental advances our understanding biology, key knowledge gaps remain. These include precise delineation replication mechanisms, detailed explanation molecular basis inter-species transmission barriers, structural definition neurotoxic species. Central addressing these questions is determination structure. While high-resolution ex vivo once seemed unlikely, recent cryo-electron microscopy (cryo-EM) computational methods for 3D reconstruction amyloids have now made this possible. Recently, near-atomic resolution structures highly infectious, from hamster 263K mouse RML were reported. The a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture provides foundation strain diversity mammals. Here, we review new findings discuss directions future research.

Language: Английский

Citations

29
α-Synuclein Conformational Strains as Drivers of Phenotypic Heterogeneity in Neurodegenerative Diseases DOI Open Access
Raphaella W. L. So, Joel C. Watts

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 168011 - 168011

Published: Feb. 14, 2023

Language: Английский

Citations

17
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

7
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
Sensitive detection of pathological seeds of α-synuclein, tau and prion protein on solid surfaces DOI Creative Commons
Christina D. Orrú, Bradley R. Groveman, Andrew G. Hughson

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(4), P. e1012175 - e1012175

Published: April 19, 2024

Prions or prion-like aggregates such as those composed of PrP, α-synuclein, and tau are key features proteinopathies prion, Parkinson’s Alzheimer’s diseases, respectively. Their presence on solid surfaces may be biohazardous under some circumstances. PrP prions bound to solids detectable by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays if the can immersed in assay wells transferred pads. Here we show that seeds remain steel wires for at least a year, even after enzymatic cleaning sterilization. We also contamination larger objects with pathological tau, detected simply assaying sampling medium has been transiently applied surface. Human α-synuclein dementia Lewy bodies brain tissue were RT-QuIC drying dilutions concentrations low 10 −6 onto stainless steel. Tau seeding activity exposed disease diluted much billion fold. Prion plates extreme −5 –10 −8 from prion-affected humans, sheep, cattle cervids. Sampling collected surgical instruments used necropsies sporadic Creutzfeldt-Jakob disease-infected transgenic mice was positive down dilution. Sensitivity prion detection not sacrificed omitting recombinant substrate during its application surface subsequent storage long added prior performing reaction. Our findings demonstrate practical prototypic protocols highly sensitive pathologic objects.

Language: Английский

Citations

5
Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis DOI Creative Commons
Binh A. Nguyen, Virender Singh, Shumaila Afrin

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 27, 2024

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This is facilitated by mutations ATTRv amyloidosis, or aging ATTRwt amyloidosis. exhibits extreme phenotypic variability, whereas presentation consistent predictable. Previously, we found unique structural variabilities cardiac polyneuropathic ATTRv-I84S patients. In contrast, five genotypically different patients with cardiomyopathy mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it necessary to study multiple sharing genotype phenotype. Here show cryo-electron microscopy structures extracted four cardiomyopathic Our confirms they share identical conformations minimal their homogenous clinical presentation. contributes understanding biopathology calls for further studies. Cryo-EM analysis reveals variability. finding biopathology.

Language: Английский

Citations

5