Amyloid structure determination in RELION-3.1

Acta Crystallographica Section D Structural Biology, Год журнала: 2020, Номер 76(2), С. 94 - 101

Опубликована: Янв. 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.

Язык: Английский

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Cryo-EM structures of four polymorphic TDP-43 amyloid cores

Nature Structural & Molecular Biology, Год журнала: 2019, Номер 26(7), С. 619 - 627

Опубликована: Июнь 24, 2019

Язык: Английский

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Cryo-EM structures of tau filaments

Current Opinion in Structural Biology, Год журнала: 2020, Номер 64, С. 17 - 25

Опубликована: Июнь 27, 2020

Язык: Английский

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Structure of pathological TDP-43 filaments from ALS with FTLD

Nature, Год журнала: 2021, Номер 601(7891), С. 139 - 143

Опубликована: Дек. 8, 2021

Язык: Английский

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Neuropathology and molecular diagnosis of Synucleinopathies

Molecular Neurodegeneration, Год журнала: 2021, Номер 16(1)

Опубликована: Дек. 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.

Язык: Английский

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

eLife, Год журнала: 2022, Номер 11

Опубликована: Март 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.

Язык: Английский

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

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Дек. 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.

Язык: Английский

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

Current Opinion in Structural Biology, Год журнала: 2019, Номер 60, С. 7 - 16

Опубликована: Ноя. 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.

Язык: Английский

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Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Ноя. 1, 2019

Abstract ATTR amyloidosis is one of the worldwide most abundant forms systemic amyloidosis. The disease caused by misfolding transthyretin protein and formation amyloid deposits at different sites within body. Here, we present a 2.97 Å cryo electron microscopy structure fibril purified from tissue patient with hereditary Val30Met consists single protofilament that formed an N-terminal C-terminal fragment transthyretin. Our provides insights into mechanism implies early state unfolded molecules, which upon proteolysis converts mature fibrils.

Язык: Английский

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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 8285 - 8307

Опубликована: Июнь 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.

Язык: Английский

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