Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 523 records · Page 29Linked to original sources

bioRxiv2024

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness

During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyers patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 pathway as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells. One sentence summaryRag-GTPases restrain TFEB/TFE3 to prevent abnormal mitophagy, maintain mitochondrial fitness, and support B cell development, Peyers patch germinal center formation, and T-independent humoral immunity.

immunology↗

bioRxiv2024

Ribonanza: deep learning of RNA structure through dual crowdsourcing

Prediction of RNA structure from sequence remains an unsolved problem, and progress has been slowed by a paucity of experimental data. Here, we present Ribonanza, a dataset of chemical mapping measurements on two million diverse RNA sequences collected through Eterna and other crowdsourced initiatives. Ribonanza measurements enabled solicitation, training, and prospective evaluation of diverse deep neural networks through a Kaggle challenge, followed by distillation into a single, self-contained model called RibonanzaNet. When fine tuned on auxiliary datasets, RibonanzaNet achieves state-of-the-art performance in modeling experimental sequence dropout, RNA hydrolytic degradation, and RNA secondary structure, with implications for modeling RNA tertiary structure.

biophysics↗

bioRxiv2024

High performance TadA-8e derived cytosine and dual base editors with undetectable off-target effects in plants

Cytosine base editors (CBEs) and adenine base editors (ABEs) are powerful tools to install precise C-to-T and A-to-G base edits in living organisms. In recently years, a highly efficient ABE based on engineered TadA-8e, known as ABE8e, has been developed to confer highly efficient A-to-G editing in mammalian cells and plants. Interestingly, TadA-8e can be further evolved and engineered to confer cytosine base editing. In this study, we compare in rice and tomato cells a serial of engineered CBEs derived from TadA-8e and identify TadCBEa, TadCBEd, and TadCBEd_V106W as efficient CBEs with high editing purity, while maintaining the relatively narrow editing window of ABE8e. Excitingly, we show TadDE is a new class of dual base editor where a single deaminase domain promotes simultaneous C-to-T and A-to-G base editing in plant cells. Multiplexed base editing is demonstrated in transgenic rice plants with TadCBEa and TadDE. Furthermore, no off-target effects of TadCBEa and TadDE can be detected by whole genome and transcriptome sequencing of the transgenic lines, suggesting high editing specificity. Finally, we demonstrate two gain-of-function crop engineering applications in rice by using the efficient dual base editor, TadDE. In the first case, herbicide resistance alleles of OsALS are introduced by TadDE. In the second case, synonymous mutations are generated in OsSPL14, making its transcript resistant to OsMIR156-mediated degradation. Together, this study reports TadA-8e derived CBEs and a dual base editor with high editing activity, purity, and specificity. They are valuable additions to the expanding plant base editing toolbox.

molecular biology↗

bioRxiv2024

Transcriptome sequencing and bioinformatics analysis of kidney tissue in a tree shrew model of calcium oxalate nephrolithiasis

BackgroundKidney stones, predominantly composed of calcium oxalate, are a prevalent and recurrent urological condition. Given their high incidence and recurrence rates, understanding their pathogenesis and identifying effective treatment strategies are imperative. MethodsIn this study, we established a calcium oxalate nephrolithiasis model using tree shrews, a primate-like animal species. When compared to commonly used rodent models (rats and mice), the tree shrew model demonstrated superior reproducibility and relevance. And leveraging transcriptome sequencing and comprehensive bioinformatics analysis. Resultswe identified 1,927 differentially expressed genes, including 1,450 upregulated and 476 downregulated genes. Furthermore, we annotated these genes to 41 KEGG enriched pathways and 1,413 GO enrichments, encompassing 1276 Biological Processes, 72 Cellular Components, and Molecular Functions. Notably, we prioritized the top 50 core genes that could potentially underlie the pathogenesis of calcium oxalate nephrolithiasis. ConclusionsOur findings establish the tree shrew as a relevant model for studying kidney stone formation and provide valuable insights into the underlying molecular mechanisms. These insights hold promise for the development of novel therapeutic strategies to address this significant health burden.

genomics↗

bioRxiv2024

GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks

Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, the regulation of the open and condensed chromatin architecture is still unclear. In this study, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and R-loop-dependent manner, to promote histone deacetylation and chromatin condensation, creating a temporal boundary between open and closed chromatin. This boundary is necessary for correct DNA end resection termination. The lack of the GATAD2B-NuRD complex leads to chromatin hyper-relaxation and extended DNA end resection, resulting in HR repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and chromatin landscape and underscore its biological significance in the RNA-dependent DNA damage response.

molecular biology↗

bioRxiv2024

Hosts Manipulate Lifestyle Switch and Pathogenicity Heterogeneity of Opportunistic Pathogens in the Single-cell Resolution

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens Serratia marcescens utilizing the Drosophila and bacterium model system. First, we find that Drosophila larvae efficiently outcompete S. marcescens and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore, Drosophila larvae reshape the transcriptomic and metabolic profiles of S. marcescens characterized by a lifestyle switch. More important, the host alters pathogenicity and heterogeneity of S. marcescens in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of S. marcescens to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.

microbiology↗

bioRxiv2024

Architecture of intact mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.

cell biology↗

bioRxiv2024

Modeling Normal Mouse Uterine Contraction and Placental Perfusion with Non- invasive Longitudinal Dynamic Contrast Enhancement MRI

The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individuals entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. Non-invasive imaging that can longitudinally probe murine placental health in vivo are critical to understanding placental development throughout pregnancy. We developed advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. We developed a dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) pipeline combined with advanced image process methods to model uterine contraction and placental perfusion dynamics. Our novel imaging pipeline uses subcutaneous administration of gadolinium for steepest-slope based perfusion evaluation. This enables non-invasive longitudinal monitoring. Additionally, we advance the placental perfusion chamber paradigm with a novel physiologically-based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and continuing remodeling throughout gestation. Lastly, using optic flow to quantify placental motions arisen from uterine contractions in conjunction with time-frequency analysis, we demonstrated that the placenta exhibited asymmetric contractile motion.

systems biology↗

bioRxiv2024

The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated beta-catenin degradation and through a mechanism independent of beta-catenin stability

WNT/{beta}-catenin signaling is mediated by the transcriptional coactivator {beta}-catenin (CTNNB1). CTNNB1 abundance is regulated by phosphorylation and proteasomal degradation promoted by a destruction complex composed of the scaffold proteins APC and AXIN1 or AXIN2, and the kinases CSNK1A1 and GSK3A or GSK3B. Loss of CSNK1A1 increases CTNNB1 abundance, resulting in hyperactive WNT signaling. Previously, we demonstrated that the HECT domain ubiquitin ligase HUWE1 is necessary for hyperactive WNT signaling in HAP1 haploid human cells lacking CSNK1A1. Here, we investigate the mechanism underlying this requirement. In the absence of CSNK1A1, GSK3A/GSK3B still phosphorylated a fraction of CTNNB1, promoting its degradation. HUWE1 loss enhanced GSK3A/GSK3B-dependent CTNNB1 phosphorylation, further reducing CTNNB1 abundance. However, the reduction in CTNNB1 caused by HUWE1 loss was disproportionately smaller than the reduction in WNT target gene transcription. To test if the reduction in WNT signaling resulted from reduced CTNNB1 abundance alone, we engineered the endogenous CTNNB1 locus in HAP1 cells to encode a CTNNB1 variant insensitive to destruction complex-mediated phosphorylation and degradation. HUWE1 loss in these cells reduced WNT signaling with no change in CTNNB1 abundance. Genetic interaction and overexpression analyses revealed that the effects of HUWE1 on WNT signaling were not only mediated by GSK3A/GSK3B, but also by APC and AXIN1. Regulation of WNT signaling by HUWE1 required its ubiquitin ligase activity. These results suggest that in cells lacking CSNK1A1, a destruction complex containing APC, AXIN1 and GSK3A/GSK3B downregulates WNT signaling by phosphorylating and targeting CTNNB1 for degradation. HUWE1 enhances WNT signaling by antagonizing this activity. Therefore, HUWE1 enhances WNT/CTNNB1 signaling through two mechanisms, one that regulates CTNNB1 abundance and another that is independent of CTNNB1 stability. Coordinated regulation of CTNNB1 abundance and an independent signaling step by HUWE1 would be an efficient way to control WNT signaling output, enabling sensitive and robust activation of the pathway. Author SummaryThe WNT pathway is a conserved signaling system with diverse functions in embryonic development and adult tissue homeostasis. Dysregulation of WNT signaling drives many types of cancer. Over four decades of research have revealed a great deal about how the core components of the WNT pathway regulate signaling, but much less is known about additional regulatory layers superimposed on the core signaling module. In this study we present an example of such regulation by the ubiquitin ligase HUWE1. Phosphorylation of the transcriptional co-activator {beta}-catenin by a protein complex called the destruction complex targets {beta}-catenin for degradation. This is considered the main regulated step in WNT signaling. We demonstrate that HUWE1 enhances WNT signaling through two distinct mechanisms. First, HUWE1 antagonizes the phosphorylation and degradation of {beta}-catenin by the destruction complex. Second, HUWE1 enhances WNT signaling through a mechanism independent from control of {beta}-catenin stability. The effects of HUWE1 on WNT signaling require its ubiquitin ligase activity, suggesting there is a HUWE1 substrate awaiting discovery. Our work therefore reveals a new role for HUWE1 controlling the main regulated step in WNT signaling - {beta}-catenin phosphorylation by the destruction complex - and most likely a downstream mechanism.

genetics↗

bioRxiv2024

BERTE：High-precision hierarchical classification of transposable elements by a transfer learning method with BERT pre-trained model and convolutional neural network

Transposable Elements (TEs) are abundant repeat sequences found in living organisms. They play a pivotal role in biological evolution and gene regulation and are intimately linked to human diseases. Existing TE classification tools can classify classes, orders, and superfamilies concurrently, but they often struggle to effectively extract sequence features. This limitation frequently results in subpar classification results, especially in hierarchical classification. To tackle this problem, we introduced BERTE, a tool for TE hierarchical classification. BERTE encoded TE sequences into distinctive features that consisted of both attentional and cumulative k-mer frequency information. By leveraging the multi-head self-attention mechanism of the pre-trained BERT model, BERTE transformed sequences into attentional features. Additionally, we calculated multiple k-mer frequency vectors and concatenate them to form cumulative features. Following feature extraction, a parallel Convolutional Neural Network (CNN) model was employed as an efficient sequence classifier, capitalizing on its capability for high-dimensional feature transformation. We evaluated BERTEs performance on filtered datasets collected from 12 eukaryotic databases. Experimental results demonstrated that BERTE could improve the F1-score at different levels by up to 21% compared to current state-of-the-art methods. Furthermore, the results indicated that not only could BERT better characterize TE sequences in feature extraction, but also that CNN was more efficient than other popular deep learning classifiers. In general, BERTE classifies TE sequences with greater precision. BERTE is available at https://github.com/yiqichen-2000/BERTE.

bioinformatics↗

bioRxiv2024

Comprehensive Hierarchical Classification of Transposable Elements based on Deep Learning

Transposable elements (TEs) are DNA sequences capable of translocating within a genome. They constitute a substantial portion of eukaryotic genomes and play significant roles in genome evolution and gene regulation. The correct classification of these repetitive elements is essential to investigate their potential impact on genomes. Despite the existence of several tools for TE classification, they often neglect the importance of simultaneously utilizing global and local information for TE-type identification, resulting in suboptimal performance. Furthermore, these tools are not user-friendly due to the complex installation processes and numerous dependencies. In this study, we introduced a novel framework, CREATE, which leverages the strengths of Convolutional and Recurrent Neural NEtworks, combined with Attention mechanisms, for efficient TE classification. Given the tree-like structure of TE groups, we separately trained nine models within the class hierarchy. Benchmarking experiments showed that CREATE significantly outperformed other TE classification tools. The source code and demo data for CREATE are available at https://github.com/yangqi-cs/CREATE. To facilitate TE annotation for researchers, we have developed a web platform, named WebDLTE, based on the CREATE framework. This platform employs GPU-accelerated pre-trained deep learning models for real-time TE classification and offers the most comprehensive collection of TEs for download. The web interface can be accessed at https://www.webdlte.nwpu.edu.cn.

bioinformatics↗

bioRxiv2024

A robust and inducible precise genome editing via an all-in-one prime editor in human pluripotent stem cells

Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small deletions, or insertions at a specific genomic locus, a strategy that shows great promise for creating "Disease in a dish" models. To improve the effectiveness of prime editing in hPSCs, we systematically compared and combined the "inhibition of mismatch repair pathway and p53" on top of the "PEmax" to generate an all-in-one "PE-Plus" prime editor. We show that PE-Plus conducts the most efficient editing among the current PE tools in hPSCs. We further established an inducible prime editing platform in hPSCs by incorporating the all-in-one PE vector into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells. By evaluating disease-associated mutations, we show that this platform allows efficient creation of both monoallelic and biallelic disease-relevant mutations in hPSCs. In addition, this platform enables the efficient introduction of single or multiple edits in one step, demonstrating potential for multiplex editing. Therefore, our method presents an efficient and controllable multiplex prime editing tool in hPSCs and their differentiated progeny.

cell biology↗

bioRxiv2024

Characterisation of anhydro-sialic acid transporters from mucosa-associated bacteria

Sialic acid (Sia) transporters are critical to the capacity of host-associated bacteria to utilise sialic acid for growth and/or cell-surface modification. While N-acetyl-neuraminic acid (Neu5Ac)-specific transporters have been studied extensively, little is known on transporters dedicated to anhydro-sialic acid forms such as 2,7-anhydro-Neu5Ac (2,7-AN) or 2,3-dehydro-2-deoxy-Neu5Ac (Neu5Ac2en). Here, we used a Sia-transport-null strain of Escherichia coli to investigate the function of members of anhydro-Sia transporter families previously identified by computational studies. First, we showed that the transporter NanG, from the Glycoside-Pentoside-Hexuronide:cation symporter family, is a specific 2,7-AN transporter, and identified by mutagenesis a crucial functional residue within the putative substrate-binding site. We then demonstrated that NanX transporters, of the Major Facilitator Superfamily, also only transport 2,7-AN and not Neu5Ac2en nor Neu5Ac. Finally, we provided evidence that SiaX transporters, of the Sodium-Solute Symporter superfamily, are promiscuous Neu5Ac/Neu5Ac2en transporters able to acquire either substrate equally well. The characterisation of anhydro-Sia transporters expands our current understanding of prokaryotic Sia metabolism within host-associated microbial communities.

microbiology↗

bioRxiv2024

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Tumor-associated macrophages (TAMs) are a crucial factor in reprogramming the tumor microenvironment following radiotherapy. The mechanisms underlying this process remain to be elucidated. Here, we seek to investigate the effects of hypofractionated radiotherapy on macrophages dynamics in a subcutaneous Lewis lung carcinoma murine model. Utilizing single-cell RNA sequencing, we identified a distinct M2-like population of macrophages with high Ccl8 expression level post-hypofractionated radiotherapy. Remarkbly, hypofractionated radiotherapy promoted CCL8high macrophages infiltration and reprogrammed them by upregulating immunosuppressive genes and downregulating antigen-presenting genes, leading to an immunosuppressive tumor microenvironment. Further, we demonstrated that hypofractionated radiotherapy amplified the CCL signaling pathway, enhancing the pro-tumorigenic functions of CCL8high macrophages and promoting macrophages recruitment. The combination therapy of hypofractionated radiotherapy with the CCL signal inhibitor Bindarit was effective in reducing M2 macrophages infiltration and extending the duration of local tumor control. This research highlights the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.

immunology↗

bioRxiv2024

Mitochondrial ncRNA LDL-805 declines in alveolar epithelial type 2 cells of chronic obstructive pulmonary disease patients.

RationaleWe showed that levels of a murine mitochondrial noncoding RNA, mito-ncR-LDL805, increase in alveolar epithelial type 2 cells exposed to extracts from cigarette smoke. The transcripts translocate to the nucleus, upregulating nucleus-encoded mitochondrial genes and mitochondrial bioenergetics. This response is lost after chronic exposure to smoke in a mouse model of chronic obstructive pulmonary disease. ObjectivesTo determine if mito-ncR-LDL805 plays a role in human disease, this study aimed to (i) identify the human homologue, (ii) test if the smoke-induced response occurs in human cells, (ii) determine causality between the subcellular localization of the transcript and increased mitochondrial bioenergetics, and (iii) analyze mito-ncR-LDL805 transcript levels in samples from patients with chronic obstructive pulmonary disease. MethodsLevels and subcellular localization of the human homologue identified from an RNA transcript library were assessed in human alveolar epithelial type 2 cells exposed to smoke extract. Lipid nanoparticles were used for nucleus-targeted delivery of mito-ncR-LDL805 transcripts. Analyses included in situ hybridization, quantitative PCR, cell growth, and Seahorse mitochondrial bioenergetics assays. Measurements and Main ResultsThe levels of human homologue transiently increased and the transcripts translocated to the nuclei in human cells exposed to smoke extract. Targeted nuclear delivery of transcripts increased mitochondrial bioenergetics. Alveolar cells from humans with chronic obstructive pulmonary disease had reduced levels of the mito-ncR-LDL805. Conclusionsmito-ncR-LDL805 mediates mitochondrial bioenergetics in murine and human alveolar epithelial type 2 cells in response to cigarette smoke exposure, but this response is likely lost in diseases associated with chronic smoking, such as chronic obstructive pulmonary disease, due to its diminished levels. ImpactThis study describes a novel mechanism by which epithelial cells in the lungs adapt to the mitochondrial stress triggered by exposure to cigarette smoke. We show that a noncoding RNA in mitochondria is upregulated and translocated to the nuclei of alveolar epithelial type 2 cells to trigger expression of genes that restore mitochondrial bioenergetics. Mitochondria function and levels of the noncoding RNA decrease under conditions that lead to chronic obstructive pulmonary disease, suggesting that the mitochondrial noncoding RNA can serve as potential therapeutic target to restore function to halt disease progression.

cell biology↗

bioRxiv2024

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the of AD-BXD Mouse Population

Alzheimers disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

neuroscience↗

bioRxiv2024

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

cell biology↗

bioRxiv2024

Suppression of epileptic seizures by transcranial activation of K+-selective channelrhodopsin

Optogenetics is a valuable tool for studying the mechanisms of neurological diseases and is now being developed for therapeutic applications. In rodents and macaques, improved channelrhodopsins have been applied to achieve transcranial optogenetic stimulation. While transcranial photoexcitation of neurons has been achieved, noninvasive optogenetic inhibition for treating hyperexcitability-induced neurological disorders has remained elusive. There is a critical need for effective inhibitory optogenetic tools that are highly light-sensitive and capable of suppressing neuronal activity in deep brain tissue. In this study, we developed a highly sensitive K+-conductive channelrhodopsin (hsKCR) by molecular engineering of the recently discovered Hyphochytrium catenoides kalium (potassium) channelrhodopsin 1. Transcranial activation of hsKCR significantly prolongs the time to the first seizure, increases survival, and decreases seizure activity in several mouse epileptic models. Our approach for transcranial optogenetic inhibition of neural hyperactivity may be adapted for cell type-specific neuromodulation in both basic and preclinical settings.

neuroscience↗