Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy DOI
Shengnan Zhang, Juan Li, Qianhui Xu

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(8), P. 4473 - 4484

Published: Feb. 16, 2023

Many amyloid fibrils associated with neurodegenerative diseases consist of an ordered fibril core (FC) and disordered terminal regions (TRs). The former represents a stable scaffold, while the latter is rather active in binding various partners. Current structural studies mainly focus on FC since high flexibility TRs hinders characterization. Here, by combining insensitive nuclei enhanced polarization transfer-based 1H-detected solid-state NMR cryo-EM, we explored intact structure α-syn including both further studied conformational dynamics upon to lymphocyte activation gene 3 (LAG3)─a cell surface receptor that involved transmission brains. We found N- C-TRs are free featuring similar conformation ensembles as those soluble monomers. While presence D1 domain LAG3 (L3D1), C-TR directly binds L3D1, meanwhile N-TR folds into β-strand integrates FC, which leads alteration overall property. Our work reveals synergistic transition intrinsically α-syn, sheds light mechanistic understanding essential role regulating pathology fibrils.

Language: Английский

Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson’s Disease DOI Open Access

Tahereh Sohrabi,

Behnaz Mirzaei-Behbahani,

Ramin Zadali

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 167992 - 167992

Published: Feb. 2, 2023

Language: Английский

Citations

43
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

43
Molecular Crowding: The History and Development of a Scientific Paradigm DOI Creative Commons
Caterina Alfano, Yann Fichou, Klaus Huber

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(6), P. 3186 - 3219

Published: March 11, 2024

It is now generally accepted that macromolecules do not act in isolation but "live" a crowded environment, is, an environment populated by numerous different molecules. The field of molecular crowding has its origins the far 80s became only end 90s. In present issue, we discuss various aspects are influenced and need to consider effects. This Review meant as introduction theme analysis evolution concept through time from colloidal polymer physics more biological perspective. We introduce themes will be thoroughly treated other Reviews issue. our intentions, each may stand itself, complete collection aspiration provide complementary perspectives propose holistic view crowding.

Language: Английский

Citations

37
Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy DOI Creative Commons
Binh A. Nguyen, Virender Singh, Shumaila Afrin

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 17, 2024

Abstract ATTR amyloidosis is caused by the deposition of transthyretin in form amyloid fibrils virtually every organ body, including heart. This systemic leads to a phenotypic variability that has not been molecularly explained yet. In brain conditions, previous studies suggest an association between clinical phenotype and molecular structures their fibrils. Here we investigate whether there such ATTRv patients carrying mutation I84S. Using cryo-electron microscopy, determined cardiac extracted from three ATTRv-I84S mutation, associated with consistent phenotype. We found each patient, exhibited different local conformations, these variations can co-exist within same fibril. Our finding suggests one disease may associate multiple fibril amyloidoses, calling for further studies.

Language: Английский

Citations

31
O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology DOI Creative Commons
Aaron T. Balana, Anne‐Laure Mahul‐Mellier, Binh A. Nguyen

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(5), P. 646 - 655

Published: Feb. 12, 2024

Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron microscopy, diminished activity seeding-based neuronal rodent models disease. Although mechanisms underpinning neutralization O-GlcNAc-modified fibrils remain unclear, our vitro mechanistic studies indicate heat shock interactions inhibit their activity, suggesting may alter interactome ways lead reduce vivo. Our show posttranslational modifications, modification, key pathogenicity.

Language: Английский

Citations

28
Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue DOI Creative Commons
Dhruva Dhavale,

Alexander M. Barclay,

Collin G. Borcik

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 29, 2024

Abstract The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation alpha-synuclein (Asyn) fibrils in bodies neurites. Here we develop validate a method to amplify Asyn extracted from LBD postmortem tissue samples use solid state nuclear magnetic resonance (SSNMR) studies determine atomic resolution structure. Amplified comprise mixture single protofilament two with very low twist. fold highly similar determined by recent cryo-electron microscopy study for minority population twisted tissue. These results expand structural characterization approaches studying mechanisms, imaging agents therapeutics targeting Asyn.

Language: Английский

Citations

28
Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures DOI Creative Commons
Jin‐Jian Hu, Wencheng Xia,

Shuyi Zeng

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 27, 2024

Abstract α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson’s disease and serves as pathological hallmark this condition. Different posttranslational modifications have been identified at multiple sites α-synuclein, influencing its conformation, aggregation function. Here, we investigate how disease-related phosphorylation O-GlcNAcylation same α-synuclein site (S87) affect fibril structure neuropathology. Using semi-synthesis, obtained homogenous monomer with site-specific (pS87) (gS87) S87, respectively. Cryo-EM revealed pS87 gS87 form two distinct structures. The GlcNAc situated S87 establishes interactions K80 E61, inducing a unique iron-like fold molecule on iron handle. Phosphorylation prevents lengthy C-terminal region including residues 73 to 140 from incorporating into core due electrostatic repulsion. Instead, N-terminal half (1–72) takes an arch-like structure. We further show both display reduced neurotoxicity propagation activity compared unmodified fibrils. Our findings demonstrate different can produce structures, which emphasizes link between formation pathology.

Language: Английский

Citations

25
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C DOI Creative Commons
Diana Arseni, Takashi Nonaka, Max Jacobsen

et al.

Nature, Journal Year: 2024, Volume and Issue: 634(8034), P. 662 - 668

Published: Sept. 11, 2024

Language: Английский

Citations

23
Positron emission tomography tracers for synucleinopathies DOI Creative Commons
Jie Xiang, Zhentao Zhang, Shengxi Wu

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 5, 2025

Abstract Synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the aggregation of α-synuclein. Variations in brain distribution allow for differentiation among these diseases facilitate precise clinical diagnosis. However, distinguishing between synucleinopathies Parkinsonism tauopathies poses a challenge, significantly impacting drug development. Therefore, molecular imaging is crucial synucleinopathies, particularly diagnosis, assessment efficacy, disease surveillance. In recent years, advances have led to rapid development α-synuclein-specific tracers positron emission tomography (PET), most which still pre-clinical stages. Interestingly, some share similar compound skeletal structures currently undergoing optimization application. Despite this progress, there remain challenges developing α-synuclein tracers. This review summarizes findings on promising PET discusses representative compounds’ characteristics while offering suggestions further research orientation.

Language: Английский

Citations

2
Environmental Mycotoxins: A Potential Etiological Factor for Neurodegenerative Diseases? DOI

Tong Nie,

Jiefeng Li,

Li You

et al.

Toxicology, Journal Year: 2025, Volume and Issue: 511, P. 154056 - 154056

Published: Jan. 13, 2025

Language: Английский

Citations

2