How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology DOI Creative Commons

Senthil T. Kumar,

Somanath Jagannath,

Cindy François

et al.

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 146, P. 105086 - 105086

Published: Sept. 22, 2020

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved α-syn fibrillization and Lewy body (LB) formation, may also accumulate within LBs Parkinson's disease (PD) other synucleinopathies. Therefore, development of tools methods to detect quantify has become increasingly crucial for mechanistic studies understand their role PD, develop new diagnostic therapies PD The majority these rely primarily on use aggregation state-specific or conformation-specific antibodies. Given impact data knowledge generated using antibodies shaping foundation directions research, it is thoroughly characterized, specificity ability capture diverse species tested validated. Herein, we describe an antibody characterization validation pipeline allows a systematic investigation well-defined well-characterized preparations various species, including monomers, fibrils, different oligomer characterized by distinct morphological, chemical secondary structure properties. This was used characterize 18 antibodies, 16 which have been reported as conformation- oligomer-specific array techniques, immunoblot analysis (slot blot Western blot), digital ELISA assay single molecule technology surface plasmon resonance. Our results show i) none specific one particular type fibrils; ii) all were be recognized fibrillar α-syn; iii) few showed high fibrils but did not bind monomers. These findings suggest great aggregate-specific do differentiate between thus highlighting importance exercising caution when interpreting obtained underscore critical before therapeutic agents. will only improve quality reproducibility research reduce costs number failures clinic.

Language: Английский

Structures of α-synuclein filaments from multiple system atrophy DOI
Manuel Schweighauser, Yang Shi, Airi Tarutani

et al.

Nature, Journal Year: 2020, Volume and Issue: 585(7825), P. 464 - 469

Published: May 27, 2020

Language: Английский

Citations

606
Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis DOI
Phuong H. Nguyen, Ayyalusamy Ramamoorthy, Bikash R. Sahoo

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

Citations

552
Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles DOI Creative Commons
Richard M. Meade, David P. Fairlie, Jody M. Mason

et al.

Molecular Neurodegeneration, Journal Year: 2019, Volume and Issue: 14(1)

Published: July 22, 2019

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark all synucleinopathathies, including Parkinson's disease (PD), dementia with (DLB), multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes diagnostic criteria. Here we attempt to reinterpret literature, particularly in terms how structure may relate pathology. We do so context rapidly evolving field, taking account newly revealed structural information on both native forms protein, recent solid state NMR cryoEM fibril structures. discuss these new findings impact current understanding PD, where this direct field.

Language: Английский

Citations

355
Structures of α-synuclein filaments from human brains with Lewy pathology DOI
Yang Yang, Yang Shi, Manuel Schweighauser

et al.

Nature, Journal Year: 2022, Volume and Issue: 610(7933), P. 791 - 795

Published: Sept. 15, 2022

Language: Английский

Citations

286
The expanding amyloid family: Structure, stability, function, and pathogenesis DOI Creative Commons
M.R. Sawaya, Michael P. Hughes,

José A. Rodríguez

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 4857 - 4873

Published: Sept. 1, 2021

Language: Английский

Citations

279
Cryo-EM structures of tau filaments DOI
Sjors H. W. Scheres, Wenjuan Zhang, Benjamin Falcon

et al.

Current Opinion in Structural Biology, Journal Year: 2020, Volume and Issue: 64, P. 17 - 25

Published: June 27, 2020

Language: Английский

Citations

226
Neuropathology and molecular diagnosis of Synucleinopathies DOI Creative Commons
Shunsuke Koga, Hiroaki Sekiya, Naveen Kondru

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Dec. 18, 2021

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons glia, the form Lewy bodies, neurites, neuronal cytoplasmic inclusions, glial inclusions. can be divided into two major disease entities: body multiple system atrophy (MSA). Common clinical presentations Parkinson's (PD), PD with dementia, dementia bodies (DLB), while MSA has subtypes, predominant cerebellar ataxia parkinsonism. There currently no disease-modifying therapies for synucleinopathies, but information obtained from molecular genetics models that explore mechanisms conversion to oligomers insoluble fibrils offer hope eventual therapies. It remains unclear how associated distinct cellular pathologies (e.g., inclusions) what factors determine neuroanatomical cell type vulnerability. Accumulating evidence vitro vivo experiments suggests species derived "strains" having different seeding properties. Recent advancements assays, such as real-time quaking-induced (RT-QuIC) protein misfolding cyclic amplification (PMCA), not only demonstrate activity also exciting opportunities diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies recombinant or brain-derived filaments provide new insight synucleinopathies. In this review, we describe clinical, genetic neuropathologic features including a discussion evolution classification staging disease. We brief on proposed formation, well supporting existence strains MSA.

Language: Английский

Citations

211
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy DOI Creative Commons
Sofia Lövestam,

Fujiet Adrian Koh,

Bart van Knippenberg

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 4, 2022

Abundant filamentous inclusions of tau are characteristic more than 20 neurodegenerative diseases that collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures amyloid filaments from human brain revealed distinct folds characterise many different diseases. A lack laboratory-based model systems to generate these has hampered efforts uncover the molecular mechanisms underlie Here, we report in vitro assembly conditions with recombinant replicate both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest post-translational modifications modulate filament assembly, previously observed additional densities AD CTE may arise presence inorganic salts, like phosphates sodium chloride. In into disease-relevant will facilitate studies determine their roles diseases, well development compounds specifically bind or prevent formation.

Language: Английский

Citations

211
Detection of neuron-derived pathological α-synuclein in blood DOI Creative Commons
Annika Kluge,

Josina Bunk,

Eva Schaeffer

et al.

Brain, Journal Year: 2022, Volume and Issue: 145(9), P. 3058 - 3071

Published: March 25, 2022

Abstract To date, no reliable clinically applicable biomarker has been established for Parkinson’s disease. Our results indicate that a long anticipated blood test disease may be realized. Following the isolation of neuron-derived extracellular vesicles patients and non-Parkinson’s individuals, immunoblot analyses were performed to detect vesicle-derived α-synuclein. Pathological α-synuclein forms derived from neuronal could detected under native conditions significantly increased in all individuals with clearly distinguished non-disease state. By performing an seeding assay these soluble conformers amplified pathological protein folding was demonstrated. Amplified exhibited β-sheet-rich structures fibrillary appearance. study demonstrates detection plasma samples potential evolve into blood-biomarker is still lacking so far. Moreover, distribution seeding-competent within exosomes sheds new light mechanisms neurodegenerative disorders.

Language: Английский

Citations

161
Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids DOI Creative Commons
Dieter Willbold, Birgit Strodel, Gunnar F. Schröder

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(13), P. 8285 - 8307

Published: June 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Language: Английский

Citations

158