Biology subjects

Zhang, B.

Publications and source records attributed to Zhang, B..

At least 217 records · Page 12Linked to original sources

bioRxiv2024

Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance

Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis and inflammation. Here we discovered a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality, and the subsequent caspase-8-dependent inflammatory cell death. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1, accompanied by diminished cell death and reduced activation of caspase-8, Gasdermin D and E, caspase-1, as well as decreased interleukin-18 (IL-18) and IL-1{beta} production. These effects were triggered by Yersinia bacteria, or by restraining TAK1 or IKK{beta} in the presence of LPS, TNF family members, or IFN{gamma}. Consequently, animals lacking Raver1 showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes. SignificanceCaspase-8 and the kinase RIPK1 are at focal points of several inflammation and cell death pathways. Thus, a careful regulation of their actions is needed. Our work identifies the RNA splicing factor Raver1 as a critical factor directing the splicing of Ripk1 in order to modulate RIPK1/caspase-8-driven pyroptosis, apoptosis and inflammation. Raver1 is central for macrophage responses to Yersinia bacteria, initiated after blockade of kinases TAK1 and IKK, measured as activation of RIPK1, caspase-8, Gasdermin D, caspase-3, IL-1{beta} and IL-18. Importantly, Raver1 is necessary for host resistance to Yersinia infection in vivo. We propose that Raver1 is key for correct tuning of RIPK1-caspase-8 dependent processes.

immunology↗

bioRxiv2024

Green Elegance T2T: An upgraded telomere-to-telomere genome assembly and annotation of looseleaf lettuce (Lactuca sativa var. crispa)

Lettuce (Lactuca sativa L.), a globally important vegetable crop, is cultivated in various horticultural varieties. Looseleaf lettuce is one of the main varieties that are consumed. Here, we report a telomere-to-telomere (T2T) genome assembly of looseleaf lettuce (L. sativa var. crispa cv. Green Elegance). By combining the sequencing data of previously reported Green Elegance v1.2, the 42.20 Gb clean ultra-long reads produced by Oxford Nanopore Technology were used to close the gaps and upgrade the genome assembly. After filling 11 gaps in Green Elegance v1.2, the final gapless telomere-to-telomere genome assembly is 2.58 Gb in length with a contig N50 of 282.47 Mb, containing nine centromeres and 18 telomeres. The genome contained 41,375 protein-coding genes, of which 99.10% were functionally annotated. This T2T genome of looseleaf lettuce will be valuable for the identification of genetic variation and the advancement of lettuce breeding.

genomics↗

bioRxiv2024

Optimizing Neoadjuvant Treatment Response Prediction for Triple-Negative Breast Cancer Using Clinical Trial Data and Deep Auxiliary Learning

MotivationTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. Developing predictive models for TNBC treatment responses is crucial but challenging due to data scarcity and the reliance on cell line data, which limits clinical translational value. Leveraging omics data from clinical trials, particularly through auxiliary learning, offers a potential solution to enhance predictive accuracy and reduce data requirements. ResultsIn this study, we propose a new approach utilizing deep auxiliary task reweighting learning methods to automatically reweight auxiliary tasks, thereby optimizing the performance of the primary task of predicting TNBC treatment responses. We benchmark various auxiliary learning methods, including ARML, AdaLoss, GradNorm, and OL AUX, against traditional supervised machine learning algorithms and single-task learning baselines. Our results characterize the performance of auxiliary learning across various contexts, including utilizing parallel treatment arms within a multi-arm clinical trial, leveraging treatment arms from different clinical trials, and integrating multiple arms with the same treatment regimens across separate clinical trials. The last scenario also provides an opportunity for validating prediction models on an independent dataset, demonstrating the superior performance of the auxiliary learning models in predicting pathological complete response (pCR) in TNBC patients treated with standardized combinational chemotherapy with Taxane, Anthracycline, and Cyclophosphamide (TAC). Availability and ImplementationSource code and additional resources can be accessed at https://github.com/moonchangin/DeepAux TxPred TNBC.

bioinformatics↗

bioRxiv2024

Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches

Recent studies have identified a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain the least understood CAF subtype. To gain a comprehensive understanding of the origin and function apCAFs, we construct a fibroblast molecular atlas across 14 types of solid tumors. Our integration study unexpectedly reveals two distinct apCAF lineages present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF lineages. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with tertiary lymphoid structures. Additionally, we discover that both apCAF lineages can up-regulate the secreted protein SPP1, which facilitates primary tumor formation and peritoneal metastasis. Taken together, this study offers an unprecedented resolution in analyzing apCAF lineages and their spatial niches.

cancer biology↗

bioRxiv2024

Nucleosome condensate and linker DNA alter chromatin folding pathways and rates

Chromatin organization is essential for DNA packaging and gene regulation in eukaryotic genomes. While significant progresses have been made, the exact atomistic arrangement of nucleosomes remains controversial. Using a well-calibrated residue-level coarse-grained model and advanced dynamics modeling techniques, particularly the non-Markovian dynamics model, we map the free energy landscape of tetra-nucleosome systems, identify both metastable conformations and intermediate states in folding pathways, and quantify the folding kinetics. Our findings show that chromatin with 10n base pairs (bp) DNA linker lengths favor zigzag fibril structures. However, longer linker lengths destabilize this conformation. When the linker length is 10n + 5 bp, chromatin loses unique conformations, favoring a dynamic ensemble of structures resembling folding intermediates. Embedding the tetra-nucleosome in a nucleosome condensate similarly shifts stability towards folding intermediates as a result of the competition of inter-nucleosomal contacts. These results suggest that chromatin organization observed in vivo arises from the unfolding of fibril structures due to nucleosome crowding and linker length variation. This perspective aids in unifying experimental studies to develop atomistic models for chromatin. SignificanceAtomic structures of chromatin have become increasingly accessible, largely through cryo-EM techniques. Nonetheless, these approaches often face limitations in addressing how intrinsic in vivo factors influence chromatin organization. We present a structural characterization of chromatin under the combined effects of nucleosome condensate crowding and linker DNA length variation--two critical in vivo features that have remained challenging to capture experimentally. This work leverages a novel application of non-Markovian dynamical modeling, providing accurate mapping of chromatin folding kinetics and pathways. Our findings support a hypothesis that in vivo chromatin organization arises from folding intermediates advancing toward a stable fibril configuration, potentially resolving longstanding questions surrounding chromatin atomic structure.

biophysics↗

bioRxiv2024

An Open Access Resource for Marmoset Neuroscientific Apparatus

The use of the common marmoset (Callithrix jacchus) for neuroscientific inquiry has grown precipitously over the past two decades. Despite windfalls of grant support from funding initiatives in North America, Europe, and Asia to model human brain diseases in the marmoset, marmoset- specific apparatus are of sparse availability from commercial vendors and thus are often developed and reside within individual laboratories. Through our collective research efforts, we have designed and vetted myriad designs for awake or anesthetized magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), as well as focused ultrasound (FUS), electrophysiology, optical imaging, surgery, and behavior in marmosets across the age- span. This resource makes these designs openly available, reducing the burden of de novo development across the marmoset field. The computer-aided-design (CAD) files are publicly available through the Marmoset Brain Connectome (MBC) resource (https://www.marmosetbrainconnectome.org/apparatus/) and include dozens of downloadable CAD assemblies, software and online calculators for marmoset neuroscience. In addition, we make available a variety of vetted touchscreen and task-based fMRI code and stimuli. Here, we highlight the online interface and the development and validation of a few yet unpublished resources: Software to automatically extract the head morphology of a marmoset from a CT and produce a 3D printable helmet for awake neuroimaging, and the design and validation of 8-channel and 14- channel receive arrays for imaging deep structures during anatomical and functional MRI.

bioengineering↗

bioRxiv2024

Downregulation of astrocytic C3 production alleviates neuronal mitochondrial dysfunction in tauopathy models

Neuronal mitochondrial dysfunction is associated with cognitive decline in neurodegenerative disorders such as Alzheimers Disease (AD). In this study, multiple pieces of evidence proved that phosphorylated tau (p-Tau) caused mitochondrial swelling and dysfunction in neurons. In a novel in vitro newborn neurons culture system, we discovered mitochondrial swelling and dysfunction were associated with increased p-Tau, leading to necroptosis activation, which was induced by Complement C3 (C3) produced from activated astrocytes. In the in vivo tauopathy mouse models, the effects of astrocytic C3 on tau-associated mitochondrial dysfunction and necroptosis were also discovered in hippocampal newborn neurons, and we directly showed that p-Tau aggregation was associated with mitochondria swelling in the hippocampal neurons by electron microscopy analysis. In addition, we proved the ability of compound anserine, which can block Tak1-Ikk dependent NF-{kappa}B activation, to further down-regulate astrocytic C3 production and alleviate neuronal mitochondrial dysfunction in vitro and in vivo, respectively. Down-regulation of astrocyte C3-production by anserine could also rescue mortality as well as cognitive and motor functions. Our findings first reported the contribution of p-Tau on neuronal mitochondrial dysfunction and proposed the therapies that down-regulate astrocytic C3 production have a potential role in alleviating this neurotoxic effect.

neuroscience↗

bioRxiv2024

A post-translational cysteine-to-serine conversion in human and mouse insulin generates a diabetogenic neoepitope

The evolving antigenic landscape of autoimmune diabetes reflects a dynamic failure to preserve self-tolerance. Yet, how novel neoantigens emerge in humans remains incompletely understood. Here, we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes (T1D). We uncovered a microenvironment-driven Cys[->]Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin, the core {beta}-cell antigen, at the single-residue level. This transformation, which we call "C19S," arises from oxidative remodeling of insulin in stressed pancreatic islets and can also occur in inflammatory antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation as diabetes progresses. Despite involving just one amino acid, C19S is specifically recognized by HLA-DQ8-restricted, register-specific CD4+ T cells that expand in individuals with T1D. These C19S-specific CD4+ T cells lack regulatory potential but acquire a poised central memory phenotype that persists at different disease stages. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.

immunology↗

bioRxiv2024

Assessing Conformation Validity and Rationality of Deep Learning-Generated 3D Molecules

Recent advancements in artificial intelligence (AI) have revolutionized the field of 3D molecule generation. However, the lack of effective evaluation methods for 3D conformations limits further improvements. Current techniques, in order to achieve the necessary speed for evaluating large numbers of AI-generated molecules, often rely on empirical geometric metrics that do not adequately capture various conformational anomalies, or on molecular mechanics (MM) energy metrics that exhibit low accuracy and lack atomic or torsional details. To address this gap, we propose a two-stage approach that achieves both high speed and quantum mechanical (QM) level accuracy. The first stage, termed the validity test, employs an AI-derived force field to identify atoms with elevated energy resulting from implausible neighboring environments. The second stage, known as the rationality test, utilizes a deep learning network trained on data with density functional theory (DFT) accuracy to detect rotatable bonds with high torsional energies. To demonstrate the functionality of our evaluation system, we applied our approach to five recently reported 3D molecule generation AI models across 102 targets in Directory of Useful Decoys-Enhanced (DUD-E) dataset. To facilitate accessibility for the academic community, our method is available as an open-source package.

bioinformatics↗

bioRxiv2024

Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFAs) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. The most severe form is a rapidly progressing demyelinating disease called cerebral ALD or CALD. Patients with cALD have a life expectancy of 2-4 years after onset and symptoms often manifest in childhood. The other forms are adrenomyeloneuropathy or AMN, which is a slower progressing degeneration of the spinal cord, and adrenal insufficiency (Addison disease). Since the accumulation of VLCFAs are a common factor in all ALD pathologies, we identified therapeutic approach that could correct this metabolic defect. We developed a substrate reduction therapy (SRT) for ALD in the form of an inhibitor of the lipid elongase principally responsible for the generation of VLCFAs, Elovl1. This small molecule was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of ABCD1-/y mice. We used single nuclei RNA seq to identify the pathways altered in the ABCD1-/y mouse and corrected with Elovl1 inhibition. Though many lipid metabolism genes and pathways were indeed corrected, treatment with the Elovl1 inhibitor unexpectedly led to profound transcriptional changes beyond correction of pathways altered by loss of ABCD1. These data suggest that Elovl1 inhibition may have broader consequences in ABCD1-/y mice than correction of lipid homeostasis.

pharmacology and toxicology↗

bioRxiv2024

Quantifying Functional Conservation of Human and Mouse Regulatory Elements via FUNCODE

Evolutionary conservation is crucial for understanding genome functions and lays the foundation for using animal models in studying human diseases. However, conventional conservation scores based on DNA sequence evolution do not capture the dynamic biochemical activities of DNA elements, termed functional conservation. Quantifying functional conservation has been limited by the availability of functional genomic data matched across species. To address this, we developed FUNCODE, a framework for characterizing functional conservation through in silico sample matching. Applying FUNCODE to 2,595 uniformly processed datasets from the Encyclopedia of DNA Elements (ENCODE), we generated genome-wide FUNCODE scores for human and mouse regulatory elements, identifying 3.3 million functionally conserved human-mouse element pairs. We demonstrate FUNCODEs diverse applications, including annotating 78,501 novel regulatory elements, transferring 37,968 high-resolution human ENCODE Hi-C loops in immune lineages to mice, identifying conserved functional signals for disease modeling, and enhancing cross-species integration of single-cell omics data.

genomics↗

bioRxiv2024

Post-translational modifications orchestrate the intrinsic signaling bias of orphan receptor GPR52

Despite recent advances in GPCR structure and pharmacology, the regulation of GPCR activation, signaling, and functioning by diverse post-translational modifications (PTMs) has been largely unexplored. Furthermore, for a special category of self-activating orphan GPCRs, it is completely unknown whether and how specific PTMs control their unique signaling profiles and cellular functions. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G protein signaling activity and emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. Through profiling the N-glycosylation and phosphorylation patterns of the receptor and clarifying their roles in G protein versus arrestin coupling, we found these two types of PTMs in specific motifs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and thus attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein (HTT) in brain striatal cells. Thus, our study provides novel insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR via distinct PTMs in different motifs.

cell biology↗

bioRxiv2024

Development of novel flavonoid senolytics through phenotypic drug screening and drug design

Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging. Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.

cell biology↗

bioRxiv2024

Identification of lipid senolytics targeting senescent cells through ferroptosis induction

Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically -eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs and ROS levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.

cell biology↗

bioRxiv2024

Red sandstone surface microbiota: functional convergence despite taxonomic divergence under dispersal limitation and hetero selection

Understanding the role of microbiota on stone surface is essential for developing effective grottoes conservation strategies. However, ecological feature of microbial communities on stone surface have been rarely investigated systematically. In this study, we explored diversity, assembly, and functional profiles of microbial communities on the red sandstone surface of the Leshan Giant Buddha from microbial ecology perspective. The results show that Proteobacteria, Actinobacteria, Cyanobacteria, and Ascomycota are the dominant phyla. Fundamental metabolic pathways are maintained during the formation of visually distinguishable microbial communities, but gene profiles vary across microbial communities of different colors. Ecological modelling suggests that selective pressure from the harsh stone surface environment fostered the interplay of dispersal limitation and heterogeneous selection during community assembly. The assembly of visually distinct microbial communities is linked to a narrower ecological niche, higher proportion of habitat specialists, and sparser network structure. Microbial-mediated ammonium assimilation and nitrogen mineralization might be the two prominent processes that contribute to stone biodeterioration. This study deepens our understanding of the assembly mechanisms and functional potentials of microbial communities on stone cultural heritage surfaces, provides microbial ecological insights for the conservation of these cultural treasures. ImportanceMinimal systematically research on the ecological interpretation of stone biodeterioration. This study reports dispersal limitation and heterogeneous selection shape the microbial community assembly responsible for the biodeterioration of red sandstone. Furthermore, fundamental metabolic processes of microbial communities, such as ammonium assimilation and nitrogen mineralization, are identified as contributors to stone biodeterioration. This study improves our understanding of microbial community assembly and their functional roles, providing a microbial ecological basis for developing effective strategies for the conservation of stone cultural heritage.

ecology↗

bioRxiv2024

Distinct gene regulatory networks govern hematopoietic and leukemia stem cells

The underlying gene regulatory networks (GRN) that govern leukemia stem cells (LSC) in acute myeloid leukemia (AML) and hematopoietic stem cells (HSC) are not well understood. Here, we identified GRNs by integrating gene expression (GE) and chromatin accessibility data derived from functionally defined cell populations enriched for HSC and LSC. We analyzed n=32 LSC+ and n=32 LSC-cell fractions from n=22 AML patients, along with n=7 stem and n=10 progenitor enriched cell populations sorted from human umbilical cord blood (hUCB), producing a database of n{approx}17,000 transcription factor (TF) regulatory interactions for hUCB-HSPC and AML. We developed an iterative algorithm that associates the degree of chromatin openness with TF binding preferences, and the GE of candidate TF and target genes within 100kb upstream of transcription start sites. A putative regulatory structure was found to be enriched in HSC-enriched cell populations, comprising TF-target gene interactions between ETS1, EGR1, RUNX2, and ZNF683 oriented in a self-reinforcing configuration. A regulatory loop comprising FOXK1 and MEIS1, rather than the 4-factor HSC subnetwork, was detected in the LSC-specific GRN. The core HSC and LSC TF networks were extended using protein-protein interaction (PPI) data to determine connectivity with interacting genes whose expression strongly associated with LSC/HSC frequency estimates, producing a database of n=103,516 PPI target pathways. The effect of perturbing genes along the identified pathways on functional HSC and LSC frequency was predicted based on statistical regression analyses. To validate GRN predictions, we used pharmacologic and CRISPR targeting, in addition to re-examining published functional data associated with several network nodes that were predicted to impact stemness. Notably, we found that inhibition of CDK6 in AML samples markedly reduced LSC numbers as assessed in de novo serial xenotransplantation studies (fold change {approx} 10), as predicted by the LSC GRN model. Additionally, in-house CRISPR-based knockdown of ETS1 resulted in a significant decrease in HSC quiescence-associated microRNA-126 expression, and increased HSC frequency. Taken together, our models provide a comprehensive view of the underlying regulatory structures governing functional human HSC and LSC. This approach has translational potential as it can be used as a high-throughput in-silico screening tool for the systematic identification of gene targets for LSC elimination and HSC expansion.

bioinformatics↗

bioRxiv2024

Growth and defence in a unicellular microalga: the coexistence of r and K strategies

r (high reproductivity but stress-sensitive offspring) and K (low reproductivity but high stress-resistant offspring) strategies are two classical life history theories. Contrary to the belief that one species only has a single strategy (i.e., either r or K), we present experimental evidence for the coexistence of both strategies in the isogenic microalga Haematococcus lacustris. Under standard conditions, swimming vegetative cells (SVC) normally grew and divided via binary fission (r strategy) and gradually shifted into non-swimming cysts (NSC) over time. Intriguingly, unlike the prevailing notion that NSC cannot propagate under stress, they were found to reproduce via multiple fission at a barely detectable growth rate, resulting in stress-resistant, non-mobile daughter cells and demonstrating a complete life history (K strategy). Collectively, our findings indicate that H. lacustris adopts both r and K strategies throughout its life history. This research enhances the understanding of the adaptation and survival of microbial populations in changing environments.

ecology↗

bioRxiv2024

Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.

Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43{Delta}NLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43{Delta}NLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies. Significance StatementCytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.

neuroscience↗