TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model DOI Creative Commons

Cha Yang,

Gwang Bin Lee, Ling Hao

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 26, 2025

The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. has been identified as risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate role in proteinopathy, we ablated TDP-43Q331K knock-in mouse line, which expresses an ALS-linked mutation at endogenous levels. We found that deficiency leads to glial activation, Purkinje cell loss, behavioral deficits mice without inducing typical pathology. Interestingly, ablation results significant body weight gain, increased fat deposition, hepatic triglyceride (TG) accumulation mice. In addition, lipidomic transcriptome analysis shows profound alteration lipid metabolism liver TDP-43Q331KTmem106b−/− Our studies reveal novel function provide new insights into their roles An unexpected obesity phenotype altered TMEM106B-deficient metabolism, providing

Language: Английский

Automated model building and protein identification in cryo-EM maps DOI Creative Commons
Kiarash Jamali, Lukas Käll, Rui Zhang

et al.

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

Citations

239
Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee DOI Open Access
Joel N. Buxbaum, Angela Dispenzieri, David Eisenberg

et al.

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

Citations

232
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
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases DOI Creative Commons
Andrew Chang, Xinyu Xiang, Jing Wang

et al.

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

Citations

109
TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry DOI Creative Commons
Jim Baggen, Maarten Jacquemyn, Leentje Persoons

et al.

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

Citations

101
Automated model building and protein identification in cryo-EM maps DOI Creative Commons
Kiarash Jamali, Lukas Käll, Rui Zhang

et al.

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

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
Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage DOI Creative Commons

Senthil T. Kumar,

Sergey Nazarov, Sílvia Porta

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(6), P. 983 - 996

Published: May 29, 2023

Abstract Despite the strong evidence linking transactive response DNA-binding protein 43 (TDP-43) aggregation to pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge sequence structural determinants its neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit morphological features similar those brain-derived filaments. We show contain β-sheet-rich helical amyloid core is fully buried by flanking structured domains protein. demonstrate proteolytic cleavage exposure this are necessary propagating pathology enhancing seeding aggregates. Only exposed efficiently seeded endogenous in cells. These findings suggest inhibiting enzymes mediating aggregates represents viable disease-modifying strategy slow progression other proteinopathies.

Language: Английский

Citations

44
Correlating the Structure and Gene Silencing Activity of Oligonucleotide-Loaded Lipid Nanoparticles Using Small-Angle X-ray Scattering DOI Creative Commons
Michal Hammel, Yuchen Fan, Apoorva Sarode

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(12), P. 11454 - 11465

Published: June 6, 2023

With three FDA-approved products, lipid nanoparticles (LNPs) are under intensive development for delivering wide-ranging nucleic acid therapeutics. A significant challenge LNP is insufficient understanding of structure–activity relationship (SAR). Small changes in chemical composition and process parameters can affect structure, significantly impacting performance vitro vivo. The choice polyethylene glycol (PEG-lipid), one the essential lipids LNP, has been proven to govern particle size. Here we find that PEG-lipids further modify core organization antisense oligonucleotide (ASO)-loaded LNPs its gene silencing activity. Furthermore, also have found extent compartmentalization, measured by ratio disordered vs ordered inverted hexagonal phases within an ASO-lipid core, predictive silencing. In this work, propose a lower disordered/ordered correlates with stronger knockdown efficacy. To establish these findings, developed seamless high-throughput screening approach integrated automated formulation system structural analysis small-angle X-ray scattering (SAXS) TMEM106b mRNA assessment. We applied screen 54 ASO-LNP formulations while varying type concentration PEG-lipids. Representative diverse SAXS profiles were visualized using cryogenic electron microscopy (cryo-EM) help elucidation. proposed SAR was built combining data. Our methods, analysis, resulting findings on PEG-lipid be rapidly optimize other complex design space.

Language: Английский

Citations

44
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