Amyloid structure determination in RELION-3.1

Acta Crystallographica Section D Structural Biology, Journal Year: 2020, Volume and Issue: 76(2), P. 94 - 101

Published: Jan. 30, 2020

Helical reconstruction in RELION is increasingly being used to determine the atomic structures of amyloid filaments from electron cryo-microscopy (cryo-EM) images. However, because energy landscape refinements typically fraught with local optima, structure determination often difficult. This paper aims help users this process. It discusses aspects helical that are particularly relevant amyloids, it illustrates problem optima refinement and how detect them, introduces a new method calculate 3D initial models reference-free 2D class averages. By providing starting closer global optimum, makes easier. All methods described open-source distributed within RELION-3.1. Their use illustrated using publicly available data set on tau brain an individual Alzheimer's disease.

Language: Английский

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α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies

Neuroscience Letters, Journal Year: 2019, Volume and Issue: 709, P. 134316 - 134316

Published: June 3, 2019

Language: Английский

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Cryo-EM structures of tau filaments

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

Published: June 27, 2020

Language: Английский

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Neuropathology and molecular diagnosis of Synucleinopathies

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

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Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

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

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Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Dec. 4, 2019

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect phenotype. Here, we amplified aggregates from PD MSA brain extracts analyzed the conformational properties using fluorescent probes, NMR spectroscopy electron paramagnetic resonance. We also generated several vitro polymorphs. found brain-derived fibrils were structurally different to all polymorphs analyzed. Importantly, there was greater structural heterogeneity among compared those brain, possibly reflecting on variability phenotypes evident PD. Our findings have significant ramifications for use non-brain-derived studies, raise important questions regarding one disease-one strain hypothesis study α-synucleinopathies.

Language: Английский

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α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(5), P. 1511 - 1519

Published: Jan. 16, 2019

Significance Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here, we examine consequences O-GlcNAcylation on toxicity α-synuclein, aggregating protein Parkinson’s disease. α-Synuclein modified by O-GlcNAc at least nine different positions vivo, but most these modifications are unknown. use synthetic chemistry to prepare six O-GlcNAcylated forms α-synuclein show that they have largely inhibitory, site-specific, effects cellular this protein. These results suggest may be strategy prevent aggregation, which could potentially exploited for treatment.

Language: Английский

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Amyloid structures: much more than just a cross-β fold

Current Opinion in Structural Biology, Journal Year: 2019, Volume and Issue: 60, P. 7 - 16

Published: Nov. 3, 2019

In recent years our understanding of amyloid structure has been revolutionised by innovations in cryo-electron microscopy, electron diffraction and solid-state NMR. These techniques have yielded high-resolution structures fibrils isolated from patients with neurodegenerative disease, as well those formed amyloidogenic proteins vitro. The results not only show the expected cross-β structure, but also reveal that fold is unexpectedly diverse complex. Here, we discuss this diversity, highlighting dynamic regions, ligand binding motifs, cavities, non-protein components, structural polymorphism. Collectively, these variations combine to allow generic be realised three dimensions different ways, diversity may related roles disease.

Language: Английский

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Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs

Nature Structural & Molecular Biology, Journal Year: 2019, Volume and Issue: 26(11), P. 1044 - 1052

Published: Nov. 1, 2019

Language: Английский

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A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function

Nature Structural & Molecular Biology, Journal Year: 2020, Volume and Issue: 27(3), P. 249 - 259

Published: March 1, 2020

Language: Английский

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