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

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research DOI
Tanya Simuni, Lana M. Chahine, Kathleen L. Poston

et al.

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(2), P. 178 - 190

Published: Jan. 22, 2024

Language: Английский

Citations

243
The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

227
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
Mechanisms and pathology of protein misfolding and aggregation DOI
Nikolaos Louros, Joost Schymkowitz, Frédéric Rousseau

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

Citations

105
Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies DOI Creative Commons
Jie Xiang,

Youqi Tao,

Yiyuan Xia

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(16), P. 3350 - 3367.e19

Published: July 7, 2023

Language: Английский

Citations

83
Disease-specific tau filaments assemble via polymorphic intermediates DOI Creative Commons
Sofia Lövestam, David Li,

Jane L. Wagstaff

et al.

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 119 - 125

Published: Nov. 29, 2023

Abstract Intermediate species in the assembly of amyloid filaments are believed to play a central role neurodegenerative diseases and may constitute important targets for therapeutic intervention 1,2 . However, structural information about intermediate has been scarce molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy study vitro recombinant truncated tau (amino acid residues 297–391) into paired helical Alzheimer’s disease or chronic traumatic encephalopathy 3 We report formation shared first filament, with an ordered core comprising 302–316. Nuclear magnetic resonance indicates that same adopt rigid, β-strand-like conformations monomeric tau. At later time points, disappears observe many different filaments, structures depend on reaction conditions. end both reactions, most disappear cores as those from human brains remain. Our results provide insights processes primary secondary nucleation assembly, implications design new therapies.

Language: Английский

Citations

74
TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP DOI Creative Commons
Diana Arseni, Renren Chen,

Alexey G. Murzin

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 898 - 903

Published: Aug. 2, 2023

Abstract The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases amyotrophic lateral sclerosis (ALS) around half frontotemporal lobar degeneration (FTLD) 1,2 . A causal role for TDP-43 neurodegeneration is evidenced by dominantly inherited missense mutations TARDBP , the gene encoding TDP-43, that promote give rise to ALS FTLD 3–7 At least four types (A–D) with pathology (FTLD-TDP) are defined distinct brain distributions assembled associated different clinical presentations dementia 8 We previously showed, using cryo-electron microscopy, assembles into amyloid filaments type B FTLD-TDP 9 However, structures without remained unknown. Here we report microscopy from brains three individuals most common FTLD-TDP, A. formed a new fold was same across individuals, indicating this may characterize FTLD-TDP. resembles chevron badge unlike double-spiral-shaped establishing filament folds neurodegenerative conditions. structures, combination mass spectrometry, led identification two post-translational modifications citrullination monomethylation R293, indicate they facilitate formation observed structural variation individual filaments. will guide mechanistic studies assembly, as well development diagnostic therapeutic compounds proteinopathies.

Language: Английский

Citations

71
Alpha Synuclein: Neurodegeneration and Inflammation DOI Open Access
Gianluigi Forloni

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5914 - 5914

Published: March 21, 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.

Language: Английский

Citations

57
Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson’s disease DOI

Qiankun Lv,

Kang‐Xin Tao,

Xiaobo Wang

et al.

Inflammation Research, Journal Year: 2023, Volume and Issue: 72(3), P. 443 - 462

Published: Jan. 4, 2023

Language: Английский

Citations

50
New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy DOI Creative Commons
Yang Yang, Holly J. Garringer, Yang Shi

et al.

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 145(5), P. 561 - 572

Published: Feb. 27, 2023

Abstract A 21-nucleotide duplication in one allele of SNCA was identified a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion MAAAEKT after residue 22 α-synuclein, resulting protein 147 amino acids. Both wild-type and mutant proteins were present sarkosyl-insoluble material extracted from frontal cortex individual JOS examined by electron cryo-microscopy. The structures filaments, comprising either single protofilament, or pair protofilaments, revealed new fold differs folds Lewy body diseases multiple system atrophy (MSA). consists compact core, sequence which (residues 36–100 α-synuclein) is unaffected mutation, two disconnected density islands (A B) mixed sequences. There non-proteinaceous cofactor bound between core island A. resembles common substructure MSA Type I II dimeric its segment approximating C-terminal protofilaments B mimicking N-terminal arm partial similarity extends to locations their cofactor-binding sites. In vitro assembly recombinant mixture yielded distinct those filaments. Our findings provide insight possible mechanism fibrillation acids forms nucleus fold, around assemble during elongation.

Language: Английский

Citations

45