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Yang, Y.

Publications and source records attributed to Yang, Y..

At least 1,009 records · Page 56Linked to original sources

A Parameter-free Deep Embedded Clustering Method for Single-cell RNA-seq Data

Clustering analysis is widely utilized in single-cell RNA-sequencing (scRNA-seq) data to discover cell heterogeneity and cell states. While many clustering methods have been developed for scRNA-seq analysis, most of these methods require to provide the number of clusters. However, it is not easy to know the exact number of cell types in advance, and experienced determination is not always reliable. Here, we have developed ADClust, an automatic deep embedding clustering method for scRNA-seq data, which can accurately cluster cells without requiring a predefined number of clusters. Specifically, ADClust first obtains low-dimensional representation through pre-trained autoencoder, and uses the representations to cluster cells into initial micro-clusters. The clusters are then compared in between by a statistical test, and similar micro-clusters are merged into larger clusters. According to the clustering, cell representations are updated so that each cell will be pulled toward centres of its assigned cluster and similar clusters, while cells are separated to keep distances between clusters. This is accomplished through jointly optimizing the carefully designed clustering and autoencoder loss functions. This merging process continues until convergence. ADClust was tested on eleven real scRNA-seq datasets, and shown to outperform existing methods in terms of both clustering performance and the accuracy on the number of the determined clusters. More importantly, our model provides high speed and scalability for large datasets.

bioinformatics↗

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.

developmental biology↗

Air Pollution Particles Hijack Peroxidasin to Disrupt Immunosurveillance and Promote Lung Cancer

Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPMs bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of anti-tumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) - an enzyme mediating type IV collagen (Col IV) crosslinking - onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourish of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN effectively abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/473156v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@12b72b2org.highwire.dtl.DTLVardef@1770adforg.highwire.dtl.DTLVardef@6ac69corg.highwire.dtl.DTLVardef@154cce_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

Angle-Tuned Coils: Enabling Building Blocks for High Performance and Multisite TMS Systems

Coordinated whole-brain neural dynamics are essential for proper control of the functionality of different brain systems. Multisite simultaneous or sequential stimulations may provide tools for mechanistic studies of brain functions and the treatment of neuropsychiatric disorders. Conventional circular and figure-8 Transcranial Magnetic Stimulation (TMS) coils occupy a large footprint, and it is difficult to reach desired multiple stimulation locations with close proximity for comprehensive multisite stimulations. These conventional coils, limited by the depth-spread tradeoff rule, also lack the required focality for targeted stimulations. In this work, we propose and demonstrate angle-tuned TMS (AT) coils with an intrinsically reduced footprint with their geometric arrangements of stacking and angle tuning. The stimulation depth can be adjusted with the coil stacking number, and the field spread can be reduced by increasing the tilted wire-wrapping angle of the coils. With either smaller or larger diameter coils than a standard commercial figure-8 coil, we show, theoretically and experimentally, improved field decay rate and field intensity, and the reduced field spread spot size at different stimulation depths. These results indicate that the proposed novel coil establishes a better depth-spread tradeoff curve than the conventional circular and figure-8 coils. This coil design has a simple and single element structure and provides a promising solution for an improved multisite brain stimulation performance and serves as the building block of more complex coils for further depth-spread improvements.

neuroscience↗

KRAS G12D can be targeted by potent salt-bridge forming inhibitors

KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS mutation (G12D) still lacks inhibitors. Herein, we explored the formation of a salt-bridge between KRASs Asp12 residue and a series of potent inhibitors. Our ITC results show that these inhibitors bind to and inhibit both GDP-bound and GTP-bound KRAS G12D, and our crystallographic studies revealed the structural basis of inhibitor binding in the switch-II pocket, experimentally confirming the formation of a salt-bridge between the piperazine moiety of the inhibitors and the 12D residue of the mutant protein. Among KRAS family proteins and mutants, both ITC and enzymatic assays support the selectivity of the inhibitors for KRAS G12D, and the inhibitors disrupt the KRAS-CRAF interaction. We also observed inhibition of cancer cell proliferation and inhibition of MAPK signaling by a representative inhibitor (TH-Z835); however, since this was not fully dependent on KRAS mutation status, it is possible that our inhibitors may have off-target effects via non-KRAS small GTPases. Experiments with a mouse model of pancreatic cancer showed that TH-Z835 significantly reduced tumor volume and synergized with an anti-PD-1 antibody. Collectively, our study demonstrates proof-of-concept for a salt-bridge, induced-fit pocket strategy for KRAS G12D, which warrants future medicinal chemistry efforts for optimal efficacy and minimized off-target effects.

cancer biology↗

N-glycosylation modulates enzymatic activity of Trypanosoma congolense trans-sialidase

Trypanosomes cause the devastating disease trypanosomiasis, in which the action of trans-sialidase (TS) enzymes harbored on their surface is a key virulence factor. TS are N-glycosylated, but the biological functions of their glycans has remained elusive. In this study, we investigated the influence of N-glycans on the enzymatic activity and structural stability of TconTS1, a recombinant TS from the African parasite Trypanosoma congolense. The enzyme was expressed in CHO Lec1 cells, which produce high-mannose type N-glycans similar to the TS N-glycosylation pattern in vivo. MALDI-TOF MS data revealed that up to eight putative N-glycosylation sites were glycosylated. N-glycan removal via EndoHf treatment of TconTS1 led to a decrease in substrate affinity relative to the untreated enzyme, but apparently has no impact on the conversion rate. No changes in secondary structure elements of hypoglycosylated TconTS1 were observed in circular dichroism experiments. Molecular dynamics simulations provided evidence for interactions between monosaccharide units of the highly flexible N-glycans and some conserved amino acids located at the catalytic site. These interactions led to conformational changes, possibly enhancing substrate accessibility and enzyme-substrate complex stability. The here-observed modulation of catalytic activity via N-glycans represents a so far unknown structure-function relationship potentially inherent in several members of the TS enzyme family.

biochemistry↗

In vitro validation of neoantigen prediction algorithm for developing personalized cancer vaccine therapy

BackgroundThe development of personalized neoantigen-based therapeutic cancer vaccines relies on computational algorithm-based pipelines. One of the critical issues in the pipeline is obtaining higher positive predictive value (PPV) performance, i.e., how many are immunogenic when selecting the top 5 to 20 candidate neoepitopes for the vaccination. We attempted to test the PPV of a neoepitope prediction algorithm Neopepsee. MethodsSix breast cancer patients and patient-derived xenografts from three lung cancer patients and their paired peripheral blood samples were subjected to whole-exome and RNA sequencing. Neoantigen was predicted using two different algorithms (Neopepsee and pVACseq). Response of induced memory T cells to neopeptide candidates was evaluated by IFN-{gamma} Enzyme-linked immune absorbent spot (ELISpot) assays of peripheral blood mononuclear cell (PBMC) from three HLA-matched donors. Positive ELISpot response to a candidate peptide in at least 2 of 3 donor PBMC was regarded as an immunogenic response. ResultsNeopepsee predicted 159 HLA-A matched neoepitope candidates out of 898 somatic mutations in nine patients (six breast and three lung cancer patients), whereas pVACseq predicted 84 HLA-A matched candidates. A total of 26 neopeptide candidates overlapped between the two predicted candidate pools. Among the candidates, 28 (20%, 28/ 137) and 15 (20%, 15/ 75) were positive by ELISpot assay, respectively. Among 26 overlapped candidates, 20 could be tested, and 7 of them (35%) were validated by ELISpot. Neopepsee identified at least one neoepitope in 7 of 9 patients (range 0-6), compared to 6 by pVACseq (range 0-5). ConclusionAs suggested by Tumor Neoantigen Selection Alliance (TESLA), our results demonstrate low PPV of individual prediction models as well as the complementary nature of the Neopepsee and pVACseq and may help design neoepitope targeted cancer vaccines. Our data contribute a significant addition to the database of tested neoepitope candidates that can be utilized to further train and improve the prediction algorithms.

immunology↗

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Hepatitis B virus (HBV) infection is a common cause of liver diseases worldwide. Existing drugs do not effectively eliminate HBV from infected hepatocytes; thus, novel curative therapies are needed. Enveloped-particle secretion is a key but poorly studied aspect of the viral life cycle. Here, we report that GRP78 positively regulates HBV enveloped-particle secretion. GRP78 is the specific target of preS1 binding; HBV can upregulate GRP78 in liver cell lines and sera from chronic hepatitis B patients. GRP78 promoted intact HBV-particle secretion in liver cell lines and an HBV transgenic-mouse model. Some peptides screened from preS1 via phage display could inhibit viral-particle secretion by interacting with GRP78 via hydrogen bonds and hydrophobic interactions, thereby disturbing the interaction with HBV particles. These results provide insight into enveloped-particle secretion in the HBV life cycle. GRP78 might be a potential target for HBV-infection treatment via restricting GRP78-preS1 interactions to block viral-particle secretion. IMPORTANCEHBV is a major human pathogen. The virus More than 250 million n individuals globally are chronically infected with HBV and can result in the infected personsabout 800,000 die for HBV-related disease annually. The mature HBV enveloped particles containing HBs and the relaxed circular (RC) DNA genome could secreted extracellularly as virions. And these enveloped virions serves as the infectious HBV particles for initiating a complete life cycle of the virus. Here, we show the GRP78 is the specific target of preS1 binding, and it could positive regulate HBV enveloped particle secretion in cell and HBV transgenic mice model. Furthermore, several peptides screened from preS1 and Phage screening could inhibit viral particle secretion by interacting with GRP78 and disturbing its interaction with HBV, and then block the life cycle of the virus. This has important implications for our understanding of the mechanisms of antivirals that target intact HBV particles secretion.

microbiology↗

Sterilization of drug-resistant influenza virus through genetic interference: use of unnatural amino acid-engineered virions

The frequent emergence of drug resistance during the treatment of influenza A virus (IAV) infections highlights a need for effective antiviral countermeasures. Here, we present an antiviral method that utilizes unnatural amino acid-engineered drug-resistant (UAA-DR) virus. The engineered virus is generated through genetic code expansion to combat emerging drug-resistant viruses. The UAA-DR virus has unnatural amino acids incorporated into its drug-resistant protein and its polymerase complex for replication control. The engineered virus can undergo genomic segment reassortment with normal virus and produce sterilized progenies due to artificial amber codons in the viral genome. We validate in vitro that UAA-DR can provide a broad-spectrum antiviral strategy for several H1N1 strains, different DR-IAV strains, multidrug-resistant (MDR) strains, and even antigenically distant influenza strains (e.g., H3N2). Moreover, a minimum dose of neuraminidase (NA) inhibitors for influenza virus can further enhance the sterilizing effect when combating inhibitor-resistant strains, partly due to the promoted superinfection of unnatural amino acid-modified virus in cellular and animal models. We also exploited the engineered virus to achieve adjustable efficacy after external UAA administration, for mitigating DR virus infection on transgenic mice harboring the [Formula] pair, and to have substantial elements of the genetic code expansion technology, which further demonstrated the safety and feasibility of the strategy. We anticipate that the use of the UAA-engineered DR virion, which is a novel antiviral agent, could be extended to combat emerging drug-resistant influenza virus and other segmented RNA viruses.

bioengineering↗

A human monoclonal antibody potently pan-neutralizes SARS-CoV-2 VOCs by targeting RBD invariant sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.

immunology↗

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

cancer biology↗

Genome Assembly and Population Resequencing Reveal the Geographical Divergence of 'Shanmei'(Rubus corchorifolius)

Rubus corchorifolius ( Shanmei or mountain berry, 2n =14) is widely distributed in China, and its fruit has high nutritional and medicinal values. Here, we report a high-quality chromosome-scale genome assembly of Shanmei, with a size of 215.69 Mb and encompassing 26,696 genes. Genome comparisons among Rosaceae species show that Shanmei and Fupenzi (Rubus chingii Hu) are most closely related, and then is blackberry (Rubus occidentalis). Further resequencing of 101 samples of Shanmei collected from four regions in provinces of Yunnan, Hunan, Jiangxi, and Sichuan in South China reveals that the Hunan population of Shanmei possesses the highest diversity and may represent the relatively more ancestral population. Moreover, the Yunnan population undergoes strong selection based on nucleotide diversity, linkage disequilibrium, and the historical effective population size analyses. Furthermore, genes from candidate genomic regions that show strong divergence are significantly enriched in flavonoid biosynthesis and plant hormone signal transduction, indicating the genetic basis of adaptation of Shanmei to the local environments. The high-quality genome sequences and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.

genomics↗

Phylogenomic analyses using genomes and transcriptomes do not resolve relationships among major clades in Phrymaceae

Premise of the studyPhylogenomic datasets using genomes and transcriptomes provide rich opportunities beyond resolving bifurcating phylogenetic relationships. Monkeyflower (Phrymaceae) is a model system for evolutionary ecology. However, it lacks a well-supported phylogeny for a stable taxonomy and for macroevolutionary comparisons. MethodsWe sampled 24 genomes and transcriptomes in Phrymaceae and closely related families, including eight newly sequenced transcriptomes. We reconstructed the phylogeny using IQ-TREE and ASTRAL, evaluated gene tree discordance using PhyParts, Quartet Sampling, and cloudogram, and carried out phylogenetic network analyses using PhyloNet and HyDe. We searched for whole genome duplication (WGD) events using chromosome numbers, synonymous distance, and gene duplication events. Key resultsMost gene trees support the monophyly of Phrymaceae and each of its tribes. Most gene trees also support the tribe Mimuleae being sister to Phrymeae + Diplaceae + Leucocarpeae, with extensive gene tree discordance among the latter three. Despite the discordance, polyphyly of Mimulus s.l. is strongly supported, and no particular reticulation event among the Phrymaceae tribes is well supported. Reticulation likely occurred among Erythranthe bicolor and close relatives. No ancient WGD event was detected in Phrymaceae. Instead, small-scale duplications are among potential drivers of macroevolutionary diversification of Phrymaceae. ConclusionsWe show that analysis of reticulate evolution is sensitive to taxon sampling and methods used. We also demonstrate that genome-scale data do not always fully "resolve" phylogenetic relationships. They present rich opportunities to investigate reticulate evolution, and gene and genome evolution involved in lineage diversification and adaptation.

evolutionary biology↗

Efficient inhibition of cell proliferation and promotion of apoptosis requires continuous treatment with abemaciclib.

Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor (CDK4 & 6i), approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease, and with endocrine therapy (ET) for initial treatment and after progression on ET. Abemaciclib has also shown clinical activity in combination with ET in patients with high risk early BC (EBC). Here, we examined the preclinical attributes of abemaciclib and other CDK4 & 6i using biochemical and cell-based assays. In vitro, abemaciclib preferentially inhibited CDK4 kinase activity versus CDK6, resulting in inhibition of cell proliferation in a panel of BC cell lines with higher average potency than palbociclib or ribociclib. Abemaciclib showed activity regardless of HER2 amplification and phosphatidylinositol 3-kinase (PI3KCA) gene mutation status. In human bone marrow progenitor cells, abemaciclib showed lower impact on myeloid maturation than other CDK4 & 6i when tested at unbound concentrations similar to those observed in clinical trials. Continuous abemaciclib treatment provided profound inhibition of cell proliferation, and triggered senescence and apoptosis. These preclinical results support the unique efficacy and safety profile of abemaciclib observed in clinical trials.

cell biology↗

Mechanistic insights into the enhancement or inhibition of phase separation by polyubiquitin chains of different lengths or linkages

Ubiquitin-binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48- and K63-linked polyubiquitin chains, respectively. UBQLN2 is recruited to stress granules in cells and undergoes liquid-liquid phase separation (LLPS) in vitro. However, interactions with ubiquitin or multivalent K48-linked chains eliminate LLPS. Here, we found that, although some polyubiquitin chain types (K11-Ub4 and K48-Ub4) did generally inhibit UBQLN2 LLPS, others (K63-Ub4, M1-Ub4 and a designed tetrameric ubiquitin construct) significantly enhanced LLPS. Using nuclear magnetic resonance (NMR) spectroscopy and complementary biophysical techniques, we demonstrated that these opposing effects stem from differences in chain conformations, but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin binding surface significantly promoted UBQLN2 LLPS by enabling a switch between homotypically to partially heterotypically-driven phase separation. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic phase separation with ubiquitin-binding shuttles and adaptors. HighlightsO_LIUbiquitin or short polyubiquitin chains bind to phase separation-driving stickers on UBQLN2 and inhibit its phase separation whereas longer chains provide the multivalency needed to enhance UBQLN2 phase separation. C_LIO_LIPhase separation of UBQLN2 is promoted over a wide range of Ub:UBQLN2 ratios in the presence of extended M1- and K63-linked Ub4 chains, but not compact K11- and K48-linked Ub4 chains. C_LIO_LIChain conformation and accessibility of the Ub interacting surface is a driving factor of UBQLN2/polyUb co-phase separation. C_LIO_LIUBQLN2 condensates assemble during in vitro enzymatic assembly of K63-linked polyUb chains as free ubiquitin is reduced. C_LI

biophysics↗

Identification and Characterization of Stem Cells in Mammalian Esophageal Stratified Squamous Epithelia

Somatic stem cells are essential for maintenance of cell proliferation-differentiation homeostasis in organs. Despite the importance, how the esophageal epithelium that executes its self-renewal and maintenance remains elusive. In this study, using 5-bromo-2-deoxyuridine (BrdU) label-chase in rat and rat esophageal keratinocyte cell line-derived organoids together with genome-wide DNA methylation profiling and single-cell RNA sequencing (scRNA-seq), we identify slow cycling/quiescent stem cell population that contain high levels of hemidesmosome (HD)s and low levels of Wnt signaling localized spatially and randomly at the basal layer of the esophageal epithelium. Pseudo-time cell trajectory from scRNA-seq indicates that cell fates begin from quiescent basal cells (the stem cells) of the basal layer that produce proliferating and/or differentiating cells in the basal layer, which, in turn, progress into differentiating cells in the suprabasal layer, ultimately transforming into differentiated keratinocytes in the differentiated layer. Perturbations of HD component expressions and/or Wnt signaling reduce stem cell in the basal layer of esophageal keratinocyte organoids, resulting in alterations of organoid formation rate, size, morphogenesis and proliferation-differentiation homeostasis. Furthermore, we show that not only high levels of HDs and low levels of Wnt signaling but also an interplay between HD and Wnt signaling defined stem cells of the basal layer in the esophageal squamous epithelium. Hence, HDs and Wnt signaling are the critical determinants for defining stem cells of the basal layer required for proliferation-differentiation homeostasis and maintenance in the mammalian esophageal squamous epithelium.

cell biology↗

Age-dependent formation of TMEM106B amyloid filaments in human brain

Many age-dependent neurodegenerative diseases, like Alzheimers and Parkinsons, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-{beta} (A{beta}), -synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, A{beta}-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

neuroscience↗