Biology subjects

Han, X.

Publications and source records attributed to Han, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Towards understanding of allostery in MALT1: a possible role of interdomain motions as revealed by NMR and AlphaFold

Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) has emerged as an attractive target for the development of modulatory compounds, particularly in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1(PCASP-Ig3)339-719 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained largely unexplored. We present here inaugural dynamic analyses of the apo MALT1(PCASP-Ig3)339-719 form along with its mutated variant, E549A. This investigation harnessed an array of NMR relaxation techniques, including longitudinal and transverse 15N auto-relaxation, heteronuclear NOE, transverse cross-correlated relaxation and NOE measurements between side-chain methyl groups. Our findings unequivocally confirm that MALT1(PCASP-Ig3)339-719 exists solely as a monomer in solution, and demonstrate that the two domains display semi-independent movements in relation to each other. Our extensive dynamic study, covering a range of time scales, along with the assessment of diverse conformational populations for MALT1(PCASP-Ig3)339-719, by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, shed light at potential mechanisms underlying the allosteric regulation of this enzyme, and the specific importance of interdomain motions.

molecular biology↗

bioRxiv2023

Solid tumor growth depends on an intricate equilibrium of malignant cell states

Control of cell identity and number is central to tissue function, yet principles governing organization of malignant cells in tumor tissues remain poorly understood. Using mathematical modeling and candidate-based analysis, we discover primary and metastatic pancreatic ductal adenocarcinoma (PDAC) organize in a stereotypic pattern whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Leveraging lineage-tracing, we reveal the WNT-R state is transient and gives rise to the WNT-S state that is highly stable and committed to organizing malignant tissue. We further show that a subset of WNT-S cells expressing the Notch ligand DLL1 form a functional niche for WNT-R cells. Genetic inactivation of WNT secretion or Notch pathway components, or cytoablation of the WNT-S state disrupts PDAC tissue organization, suppressing tumor growth and metastasis. This work indicates PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, uncovering a fundamental principle governing solid tumor growth and revealing new opportunities for therapeutic intervention.

cancer biology↗

bioRxiv2023

High-energy demand and nutrient exhaustion in MTCH2 knockout cells

Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection from diet-induced obesity. We now show using temporal metabolomics that MTCH2 deletion results in a high ATP demand, an oxidized environment, a high lipid/amino acid/carbohydrate metabolism, and in the decrease of many metabolites. Lipidomics analyses show a strategic adaptive decrease in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, all the metabolic changes in the MTCH2 knockout cells were rescued by MTCH2 re-expression. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion inhibits adipocyte differentiation, an energy consuming reductive biosynthetic process. In summary, loss of MTCH2 results in an increase in energy demand that triggers a catabolic and oxidizing environment, which fails to fuel the anabolic processes during adipocyte differentiation.

cell biology↗

bioRxiv2023

Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain

Phospholipase C gamma-2 (PLC{gamma}2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into numerous downstream signaling pathways. PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimers disease (AD) and with longevity. In the brain, PLCG2 is highly expressed in microglia, where it is proposed to regulate phagocytosis, secretion of cytokines/chemokines, cell survival and proliferation. We analyzed the brains of three-month-old PLC{gamma}2 knockout (KO), heterozygous (HET), and wild-type (WT) mice using multiomics approaches, including shotgun lipidomics, proteomics, and gene expression profiling, and immunofluorescence. Lipidomic analyses revealed sex-specific losses of total cerebrum PIP2 and decreasing trends of DAG content in KOs. In addition, PLC{gamma}2 depletion led to significant losses of myelin-specific lipids and decreasing trends of myelin-enriched lipids. Consistent with our lipidomics results, RNA profiling revealed sex-specific changes in the expression levels of several myelin-related genes. Further, consistent with the available literature, gene expression profiling revealed subtle changes on microglia phenotype in mature adult KOs under baseline conditions, suggestive of reduced microglia reactivity. Immunohistochemistry confirmed subtle differences in density of microglia and oligodendrocytes in KOs. Exploratory proteomic pathway analyses revealed changes in KO and HET females compared to WTs, with over-abundant proteins pointing to mTOR signaling, and under-abundant proteins to oligodendrocytes. Overall, our data indicate that loss of PLC{gamma}2 has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology and aging via novel mechanisms in addition to regulation of microglia function. Significance StatementThe PLCG2 gene contains a number of rare variants linked with increased and decreased risk for Alzheimers disease and longevity, but little is known about the role of PLC{gamma}2 in normal brain function. The results described herein are significant because they describe the effects of knockout of PLC{gamma}2 on brain cell types, thus mimicking the loss of function Alzheimers disease risk mutation. Our data describe novel effects of PLC{gamma}2 deficiency on myelin homeostasis and mTOR signaling that have not been previously described that may underlie its association with Alzheimers disease pathogenesis and longevity.

neuroscience↗

bioRxiv2023

Development of a human heart-on-a-chip model using induced pluripotent stem cells, fibroblasts and endothelial cells

In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell-cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted stronger junction formation between vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The triculture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the biculture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such triculture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.

cell biology↗

bioRxiv2023

A Mouse Model of the Protease Activated Receptor 4 (PAR4) Pro310Leu Variant has Reduced Platelet Reactivity

BackgroundProtease activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated a single nucleotide polymorphism in extracellular loop 3 (ECL3), PAR4-P310L (rs2227376) leads to a hypo-reactive receptor. ObjectivesThe goal of this study was to determine how the hypo-reactive PAR4 variant in ECL3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L). MethodsA point mutation was introduced into the PAR4 gene, F2rl3, via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by IIb{beta}3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model. ResultsPAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or IIb{beta}3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis. ConclusionsPAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts. EssentialsO_LIA mouse model was created to represent the PAR4-P310L sequence variant. C_LIO_LIPAR4-P322L leads to reduced platelet reactivity in response to PAR4-activation peptide and thrombin, while the ADP and GPVI signaling pathways were unaffected. C_LIO_LIThe PAR4-P322L mutation decreases time to occlusion in a mouse model of arterial thrombosis. C_LIO_LIThe PAR4-P322L mouse model provides a foundation to further explore the role of PAR4 in hemostasis and thrombosis. C_LI

physiology↗

bioRxiv2023

FFCM-MRF: An accurate and generalizable cerebrovascular segmentation pipeline for humans and rhesus monkeys based on TOF-MRA

PurposeCerebrovascular segmentation and quantification of vascular morphological features on humans and rhesus monkeys are essential for prevention, diagnosis, and treatment of brain diseases. However, current automated whole-brain vessel segmentation methods are often not generalizable to independent datasets, limiting their usefulness in real-world environments with their heterogeneity in participants, scanners, and species. Materials and MethodsIn this study, we proposed an automated, accurate and generalizable segmentation method for magnetic resonance angiography images called FFCM-MRF. This method integrates fast fuzzy c-means clustering and Markov random field optimization using blood vessel shape priors and spatial constraints. We used a total of 123 human and 44 macaque MRA images scanned at 1.5 T, 3 T, and 7 T MRI from 9 datasets to develop and validate the method. ResultsThe average Dice score coefficients for multiple independent datasets were 69.16-89.63%, with the improvements in FFCM-MRF ranged from 0.16-16.14% compared with state-of-the-art machine learning methods. Quantitative analysis showed that FFCM-MRF can accurately segment major arteries in the Circle of Willis at the base of the brain and smaller distal pial arteries while effectively suppressing noise. Test-retest analysis showed that the model yielded high vascular volume and diameter reliability. ConclusionsOur results demonstrate that the proposed method is highly accurate and reliable and largely independent of variations in field strength, scanner platforms, acquisition parameters, and species. The macaque MRA data and user-friendly open-source toolbox are freely available at OpenNeuro and GitHub to facilitate studies of imaging biomarkers for cerebrovascular and neurodegenerative diseases.

neuroscience↗

bioRxiv2023

A large-scale volumetric correlated light and electron microscopy study localizes Alzheimer's disease-related molecules in the hippocampus

Connectomics using volume-electron-microscopy enables mapping and analysis of neuronal networks, revealing insights into neural circuit function and dysfunction. In Alzheimers disease (AD), where amyloid-{beta} (A{beta}) and hyperphosphorylated-Tau (pTau) are implicated, connectomics offers an approach to unravel how these molecules contribute to circuit alterations by enabling the study of these molecules within the context of the complete local neuronal and glial milieu. We present a volumetric-correlated-light-and-electron microscopy (vCLEM) protocol using fluorescent nanobodies to localize A{beta} and pTau within a large-scale connectomics dataset from the hippocampus of the 3xTg AD mouse model. A key outcome of this work is a publicly accessible vCLEM dataset, featuring fluorescent labeling of A{beta} and pTau in the ultrastructural context with segmented neurons, glia, and synapses. This dataset provides a unique resource for exploring AD pathology in the context of connectomics and fosters collaborative opportunities in neurodegenerative disease research. As a proof-of-principle, we uncovered new localizations of A{beta} and pTau, including pTau-positive spine-like protrusions at the axon initial segment and changes in the number and size of synapses near A{beta} plaques. Our vCLEM approach facilitates the discovery of both molecular and structural alterations within large-scale EM data, advancing connectomics research in Alzheimers and other neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Senescence of endplate osteoclasts induces sensory innervation and spinal pain

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

cell biology↗

bioRxiv2023

Deep learning-based aberration compensation improves contrast and resolution in fluorescence microscopy

Optical aberrations hinder fluorescence microscopy of thick samples, reducing image signal, contrast, and resolution. Here we introduce a deep learning-based strategy for aberration compensation, improving image quality without slowing image acquisition, applying additional dose, or introducing more optics into the imaging path. Our method (i) introduces synthetic aberrations to images acquired on the shallow side of image stacks, making them resemble those acquired deeper into the volume and (ii) trains neural networks to reverse the effect of these aberrations. We use simulations and experiments to show that applying the trained de-aberration networks outperforms alternative methods, providing restoration on par with adaptive optics techniques; and subsequently apply the networks to diverse datasets captured with confocal, light-sheet, multi-photon, and super-resolution microscopy. In all cases, the improved quality of the restored data facilitates qualitative image inspection and improves downstream image quantitation, including orientational analysis of blood vessels in mouse tissue and improved membrane and nuclear segmentation in C. elegans embryos.

bioengineering↗

bioRxiv2023

Generation of CRISPR-edited birch Plants without DNA integration using Agrobacterium-mediated Transformation Technology

CRISPR/Cas9 system has emerged as a powerful tool in genome editing; however, generation of CRISPR-edited DNA-free plants is still challenging. In this study, Betula platyphylla (birch) was used to build a method to generate CRISPR-edited plant without foreign DNA integration using Agrobacterium-mediated transformation (CPDAT method). This technique utilizes transient genetic transformation to introduce T-DNA coding gRNA and Cas9 into birch cells, and T-DNA will express to synthesize gRNA and Cas9 protein, which will form a complex to cleave the target DNA site. The genome may be mutated due to DNA repair, and these mutations will be preserved and accumulated not dependent on whether T-DNA is integrated into the genome or not. After transient transformation, birch plants were cut into explants to induce adventitious buds without antibiotic selection pressure. Each adventitious bud can be considered as an independent potentially CRISPR-edited line for mutation detection. CRISPR-edited birch plants without foreign DNA integration are further selected by screening CRISPR-edited lines without T-DNA integration. Among 65 randomly chosen independent lines, the mutation rate was 80.00% including 40.00% of lines with both alleles mutated. In addition, 5 lines out of 65 studied lines (7.69%) were CRISPR-edited birch plants without DNA integration. In conclusion, this innovative method presents a novel strategy for generating CRISPR-edited birch plants, thereby significantly enhancing the efficiency of generating common CRISPR-edited plants. These findings offer considerable potential to develop plant genome editing techniques further.

genetics↗

bioRxiv2023

Rolling 2D Bioelectronic film into 1D: a Suturable Long-term Implantable Soft Microfiber

Long-term implantable bioelectronics can efficiently evaluate the function of the nervous system. 1D fiber-shaped devices require small surgical incisions significantly benefiting long-term biocompatibility. We report a strategy of rolling to reduce the dimension of bioelectronic devices from 2D film to 1D microfiber. The soft and stretchable multifunctional microfiber accommodates more than 60-channel longitudinally-distributed electrodes for bio-electric and -mechanical monitoring. It can be sutured into muscle with tiny incision for 8-month bio-electrical monitoring in rats. Importantly, after 13-month implantation, the fibroblast encapsulation around the fiber is negligible. Moreover, it can wander inside a brain under magnetic field. This strategy not only opens up the study of multi-channel and -function soft and stretchable fiber-shaped sensors but offers a platform for minimally-invasive implantable bioelectronics. One-Sentence SummaryThe rolling enables stretchable electrode array along one single microfiber and multimodal long-term in-vivo monitoring.

neuroscience↗

bioRxiv2023

Akkermansia muciniphila identified as key strain to function in pathogen invasion and intestinal stem cell proliferation through Wnt signaling pathway

As the largest mucosal surface, the gut has built a physical, chemical, microbial and immune barrier to protect the body against pathogen invasion. The disturbance of gut microbiota aggravates pathogenic bacteria invasion and gut barrier injury. Fecal microbiota transplantation (FMT) is a promising treatment for microbiome-related disorders, where beneficial strain engraftment is a significant factor influencing FMT outcomes. The aim of this research was to explore the effect of FMT on antibiotic-induced microbiome-disordered (AIMD) model infected with enterotoxigenic Escherichia coli (ETEC). We used piglet, mouse and intestinal organoid models to explore the protective effects and mechanisms of FMT on ETEC infection. The results showed that FMT regulated gut microbiota and enhanced the protection of AIMD piglets against ETEC K88 challenge, as demonstrated by reduced intestinal pathogen colonization and alleviated gut barrier injury. Akkermansia muciniphila (A. muciniphila) and Bacteroides fragilis (B. fragilis) were identified as two strains that may play key roles in FMT. We further investigated the alleviatory effects of these two strains on ETEC infection in AIMD mice model, which revealed that A. muciniphila and B. fragilis relieved ETEC-induced intestinal inflammation by maintaining the proportion of Treg/Th17 cells and epithelial damage by moderately activating the Wnt/{beta}-catenin signaling pathway, while the effect of A. muciniphila was better than B. fragilis. We therefore identified whether A. muciniphila protected against ETEC infection using basal-out and apical-out intestinal organoid models. A. muciniphila did protect the intestinal stem cells and stimulate proliferation and differentiation of intestinal epithelium, and the protective effects of A. muciniphila was reversed by Wnt inhibitor. FMT alleviated ETEC-induced gut barrier injury and intestinal inflammation in AIMD model. A. muciniphila was identified as key strain in FMT to promote proliferation and differentiation of intestinal stem cells by mediating the Wnt/{beta}-catenin signaling pathway.

microbiology↗

bioRxiv2023

Harnessing the endogenous Type I-C CRISPR-Cas system for genome editing in Bifidobacterium breve

Bifidobacterium breve, one of the main bifidobacterial species colonizing the human gastrointestinal tract in early life, has received extensive attention for its purported beneficial effects on human health. However, exploration of the mode of action of such beneficial effects exerted by B. breve is cumbersome due to the lack of effective genetic tools, which limits its synthetic biology application. Given the widespread presence of endogenous CRISPR-Cas systems in B. breve, the current study developed an endogenous CRISPR-based gene editing toolkit for genetic manipulation of B. breve. Deletion of the gene coding uracil phosphoribosyl-transferase (upp) was achieved in two different B. breve strains using this system. In addition, translational termination of uracil phosphoribosyl-transferase was successfully achieved in B. breve FJSWX38M7 by single-base substitution of the upp gene and insertion of three stop codons. The gene encoding linoleic acid isomerase (bbi) in B. breve, being a characteristic trait, was deleted after plasmid curing, which rendered it unable to convert linoleic acid into conjugated linoleic acid, demonstrating the feasibility of successive editing. This study expanded the gene manipulation toolkit of B. breve and provides a reference for functional genome editing and analysis using an endogenous CRISPR-Cas system in Bifidobacterium. ImportanceThe lack of effective genetic tools for Bifidobacterium breve is an obstacle to studying the molecular mechanisms of its health-promoting effects, hindering the development of next-generation probiotics. Here, we introduce a gene editing method based on the endogenous CRISPR-Cas system, which can achieve gene deletion, single base substitution, gene insertion and continuous gene editing in B. breve. This study will promote the excavation of functional genes and elucidation of molecular mechanisms of B. breve.

molecular biology↗

bioRxiv2023

Src/Fas2-dependent Ephrin phosphorylation initiates Eph/Ephrin reverse signaling through Rac1 to shape columnar units in the fly brain

Columns are the morphological and functional units containing multiple neurons in the brain. The molecular mechanisms of column formation are largely unknown. Ephrin/Eph signaling mediates a variety of developmental processes. Ephrin acts as a ligand for Eph to regulate forward signaling, while Eph acts as a ligand for Ephrin to regulate reverse signaling. However, whether and how the uni- or bi-directional Ephrin/Eph signaling is involved in column formation remains elusive. In this study, we show that Ephrin and Eph regulate the morphology and location of columnar neurons through bi-directional repulsive signaling. Furthermore, Eph ligand triggers cytoplasmic tyrosine phosphorylation of Ephrin under the control of Src kinases and Fasciclin II (Fas2), forming Ephrin/Src/Fas2 complex to promote reverse signaling through a downstream regulator, Rac1. This study presents for the first time a unified picture of the molecular interactions in the defined context of column formation using the fly brain as a model.

developmental biology↗

bioRxiv2023

Geranylgeranyl pyrophosphate (GGPP) is associated with hepatic lipid accumulation and insulin resistance in MAO by prenylating Perilipin4

Metabolically Abnormal Obesity (MAO) is characterized by hepatic steatosis and type 2 diabetes (T2D), in contrast to Metabolically Healthy Obesity (MHO). In this study, we investigated the role of hepatic geranylgeranyl pyrophosphate (GGPP), a metabolite of the mevalonate (MVA) pathway, in regulating the differences in lipid metabolism between MAO and MHO. Our findings revealed that GGPP levels were significantly elevated in individuals with MAO, and deficiency of GGPP in the liver ameliorated the defects associated with MAO. Furthermore, we discovered that the prenylation of the lipid droplet-associated protein Perilipin 4 by GGPP enhances the formation of large lipid droplets, thereby exacerbating hepatic lipid accumulation and insulin resistance. Notably, the inhibitor DGBP, targeting the GGPP synthase Ggpps, effectively attenuated the traits of MAO, offering novel insights into the treatment of this condition.

pathology↗

bioRxiv2023

Inducer of CBF Expression 1 (ICE1) Promotes Cold-enhanced Immunity by Directly Activating Salicylic Acid Signaling

Cold stress affects plant immune responses, and this process may involve the salicylic acid (SA) signaling pathway. However, the underlying mechanism by which low temperature signals coordinate with SA signaling to regulate plant immunity remains not fully understood. Here, we found that low temperatures enhanced the disease resistance of Arabidopsis against Pseudomonas syringae pv. tomato (Pst) DC3000. This process required Inducer of CBF expression 1 (ICE1), the core transcription factor in cold-signal cascades. ICE1 physically interacted with Non-expresser of PR genes 1 (NPR1), the master regulator of the SA signaling pathway. Enrichment of ICE1 on the PR1 promoter and its ability to transcriptionally activate PR1 were enhanced by NPR1. Further analyses revealed that cold stress signals cooperate with SA signals to facilitate plant immunity against pathogen attack in an ICE1-dependent manner. Cold treatment promoted interactions of NPR1 and TGA3 with ICE1, and increased the ability of the ICE1-TGA3 complex to transcriptionally activate PR1. Together, our results characterize a previously unrecognized role of ICE1 as an indispensable regulatory node linking low temperature activated- and SA-regulated immunity. Discovery of a crucial role of ICE1 in coordinating multiple signals associated with immunity broadens our understanding of plant-pathogen interactions.

plant biology↗

bioRxiv2023

Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimers disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosyceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results reveal a novel function of TMEM106B interacting with galactosyceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

neuroscience↗