Structures of α-synuclein filaments from human brains with Lewy pathology

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

Published: Sept. 15, 2022

Language: Английский

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Automated model building and protein identification in cryo-EM maps

Nature, Journal Year: 2024, Volume and Issue: 628(8007), P. 450 - 457

Published: Feb. 26, 2024

Interpreting electron cryo-microscopy (cryo-EM) maps with atomic models requires high levels of expertise and labour-intensive manual intervention in three-dimensional computer graphics programs

Language: Английский

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Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee

Amyloid, Journal Year: 2022, Volume and Issue: 29(4), P. 213 - 219

Published: Oct. 2, 2022

The Nomenclature Committee of the International Society Amyloidosis met at XVIII Symposium on in September and virtually October 2022 with discussions resulting this upgraded nomenclature recommendation. principles remain unchanged but there is an ongoing discussion regarding importance varying nature intracellular protein aggregates, particularly those associated neurodegenerative diseases. Six novel proteins were added to list human amyloid fibril proteins. Of these, three are polypeptide hormones two currently utilised peptide drugs, making number known iatrogenic forms four, all appearing as subcutaneous nodules injection site. sixth transmembrane 106B protein, forming fibrils disorders frontotemporal dementia. now 42.

Language: Английский

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Emerging diagnostics and therapeutics for Alzheimer disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(9), P. 2187 - 2199

Published: Sept. 1, 2023

Language: Английский

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Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

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Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Cell, Journal Year: 2022, Volume and Issue: 185(8), P. 1346 - 1355.e15

Published: March 4, 2022

Misfolding and aggregation of disease-specific proteins, resulting in the formation filamentous cellular inclusions, is a hallmark neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that previously unsolved amyloid fibril composed 135 amino acid C-terminal fragment TMEM106B common finding distinct human diseases, including cases characterized by abnormal TDP-43, tau, α-synuclein protein. A combination cryoelectron microscopy mass spectrometry was used to solve structures fibrils at resolution 2.7 Å from postmortem brain tissue afflicted frontotemporal lobar degeneration TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, 2), dementia Lewy bodies (DLB, 1). The commonality abundant TMEM106B, lysosomal/endosomal protein, broad range debilitating disorders indicates shared fibrillization pathway may initiate accelerate neurodegeneration.

Language: Английский

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TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Cell, Journal Year: 2023, Volume and Issue: 186(16), P. 3427 - 3442.e22

Published: July 7, 2023

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, lysosomal transmembrane protein, can serve as an alternative receptor for into angiotensin-converting enzyme 2 (ACE2)-negative Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked infection, demonstrating role in viral Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), luminal domain (LD) engages receptor-binding motif spike. Finally, promotes spike-mediated syncytium formation, suggesting fusion. Together, our findings identify ACE2-independent infection mechanism involves cooperative interactions heparan sulfate TMEM106B.

Language: Английский

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Automated model building and protein identification in cryo-EM maps

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 16, 2023

Interpreting electron cryo-microscopy (cryo-EM) maps with atomic models requires high levels of expertise and labour-intensive manual intervention. We present ModelAngelo, a machine-learning approach for automated model building in cryo-EM maps. By combining information from the map protein sequence structure single graph neural network, ModelAngelo builds proteins that are similar quality as those generated by human experts. For nucleotides, backbones accuracy humans. using its predicted amino acid probabilities each residue hidden Markov searches, outperforms experts identification unknown sequences. will thus remove bottlenecks increase objectivity determination.

Language: Английский

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TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

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

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Long COVID: a review and proposed visualization of the complexity of long COVID

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: April 20, 2023

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose visual description the complexity COVID its pathogenesis that can be used by researchers, clinicians, public health officials to guide global effort toward an improved understanding eventual mechanism-based provision care afflicted patients. The proposed visualization framework for should evidence-based, dynamic, modular, systems-level approach condition. Furthermore, further research such could establish strength relationships between pre-existing conditions (or risk factors), biological mechanisms, resulting clinical phenotypes outcomes COVID. Notwithstanding significant contribution disparities in access social determinants have on disease course long our model focuses primarily mechanisms. Accordingly, sets out scientific, clinical, efforts better understand abrogate burden imposed

Language: Английский

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