Biology subjects

Patel, T.

Publications and source records attributed to Patel, T..

At least 19 recordsLinked to original sources

bioRxiv2026

MYC-Hyperactivated Osteosarcoma Models Exhibit Resistance to Cabozantinib plus TIGIT Blockade

Background: Relapsed and refractory osteosarcoma (OS) remains a major therapeutic challenge, with fewer than 20% of patients surviving beyond 3 years. Increasing evidence indicates that MYC amplification/overexpression is associated with inferior survival. Small molecule inhibitors and immunotherapies have limited single-agent efficacy in pediatric solid tumors. Using syngeneic cell lines derived from p53-driven and MYC-hyperactivated genetically engineered mouse models (GEMMs) of OS, we tested cabozantinib, a multi-tyrosine kinase inhibitor with immunomodulatory properties, with TIGIT immune checkpoint blockade and investigated mechanisms underlying therapeutic response and resistance. Methods: In vitro cabozantinib sensitivity was established in GEMM-derived cell lines. Mice bearing tibial tumors were randomized to vehicle control, cabozantinib, anti-TIGIT antibody, or combination therapy, and tumor growth and survival assessed after a 3-week treatment period. Temporal RNA sequencing was performed at early (8-15 days) and late (18-24 days) time points to characterize transcriptomic changes associated with efficacy. Results: MYC-hyperactivated cell lines were more resistant to cabozantinib in vitro than p53-driven lines (mean IC50 5.51 vs 0.65 mciroM, p=0.0016). In p53-driven orthotopic models, combination therapy significantly decreased tumor growth and improved survival compared to solvent and cabozantinib alone, while in MYC-hyperactivated models cabozantinib-containing regimens delayed tumor progression relative to control or anti-TIGIT monotherapy, however the addition of anti-TIGIT did not significantly improve survival over cabozantinib alone. Temporal transcriptomics revealed upregulated anti-tumor immune-response pathways and decreased M2 macrophages only with combination treatment in the p53-driven model. In contrast, combination-treated MYC-hyperactivated models demonstrated increased TNF signaling and elevated Cxcl5 and Ccr2 expression, indicative of increased myeloid cell recruitment, and upregulation of extracellular matrix (ECM) remodeling pathways suggest a therapy-induced stress adapted state that propagates treatment resistance over time. Conclusion: New therapies are needed for patients with relapse or refractory OS. By targeting tumor-intrinsic resistance mechanisms and modulating the tumor microenvironment using cabozantinib and anti-TIGIT therapy, improved tumor control and survival was achieved in p53-driven orthotopic OS models. MYC-hyperactivated models were able to overcome therapeutic pressure and employ myeloid recruitment and ECM remodeling programs to achieve treatment resistance. Targeting of these programs should be considered in future studies investigating therapeutic strategies in relapsed and refractory OS.

cancer biology↗

bioRxiv2026

Deep Learning-based Modeling Enhances Efficacy of Natural Ligand CAR Binders Targeting CD70

CD70 is well-recognized as a promising "pan-cancer: chimeric antigen receptor (CAR) T-cell target. Prior work has shown that a "natural ligand" (NL)-based CAR targeting CD70, employing its physiological interaction partner CD27, may have therapeutic advantages over antibody-based CARs. Yet while antibody-based CARs are routinely optimized by affinity maturation of their scFv, whether the binding sequence of an NL CAR can be engineered to improve its function remains unexplored. Here, we combined deep learning with physics-based modeling to redesign residues at the CD27:CD70 interface, identifying a CD27 variant, "N88A", which enhances the efficacy of CD70-targeting CAR T-cells across models of acute myeloid leukemia, multiple myeloma, and renal cell carcinoma. Biophysical approaches, including molecular dynamics simulations, support a mechanism of increased binder conformational freedom underlying potency enhancement. Our work presents CD27N88A CAR T-cells as a promising new therapeutic option and proposes that computational modeling could be applied to enhance efficacy of other NL-based immunotherapies.

cancer biology↗

bioRxiv2026

Life inside polymetallic nodules

Deep-sea abyssal plains harbour extensive biodiversity, much of which remains undocumented. Polymetallic nodules in the abyssal plains of the Clarion-Clipperton Zone (CCZ), Central Pacific, harbour diverse meiofaunal communities within their crevices, representing an understudied habitat. Given their high concentrations of nickel, copper, and cobalt, nodules are currently one of the primary targets for the extraction of deep-sea mineral resources. Here, we characterise the physical properties of polymetallic nodules, quantify their meiofaunal crevice communities, and compare them to those from the nearby sediments. We show that nodules contain internal cracks and microfossils, that their crevices harbour meiofaunal communities dominated by nematodes and copepods, and that faunal abundance increases significantly with nodule volume. Nodule-crevice nematode and copepod abundances were equivalent to approximately 10% and 25%, respectively, of those recorded in nearby sediments across the two exploration contract areas in the eastern CCZ. Based on 18S rRNA data, nematode and copepod assemblages recovered from nodule crevices differed from those recovered from nearby sediments collected during the same expedition and within the same exploration contract areas. Our findings, therefore, point to the possibility of nodule-associated crevice meiofauna communities and the consequent risk of biodiversity loss associated with nodule removal through potential future commercial mining.

ecology↗

bioRxiv2026

Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine levels and reduced Alzheimers disease risk.

BackgroundLactamase {beta} (LACTB) is a serine {beta}-lactamase-like mitochondrial enzyme associated with cancer progression, obesity, and lipid metabolism. LACTB is located in an Alzheimers Disease (AD) risk locus and has been associated with AD in a proteomic study. MethodsWe performed Mendelian Randomization (MR) analysis to estimate the association between LACTB expression, succinylcarnitine levels, and AD risk. We generated LACTB knock-down (KD) THP1 macrophages, LACTB knock-out (KO) iPSC-derived microglia and LACTB enzymatically-dead (ED) mice. The impact of LACTB loss-of-function in myeloid cells was characterized via transcriptomics, metabolomics, lipidomics, and functional assays. Finally, human LACTB KO microglia precursors were xenotransplanted into the brains of mice with amyloid pathology to assess in vivo interactions with amyloid plaques. ResultsMR analyses revealed that lower LACTB expression in myeloid cells may lead to reduced AD risk and higher levels of succinylcarnitine, a metabolite associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. Transcriptional and functional studies showed that loss of LACTB enhances OXPHOS, and reduces protein synthesis and triglycerides. LACTB expression was upregulated following interferon or TNF stimulation, and its loss modified efferocytosis- related functions under inflammatory conditions. In vivo, xenotransplanted human LACTB KO microglia exhibited enhanced association with amyloid plaques. ConclusionsOur findings define a previously unrecognized axis linking LACTB and succinylcarnitine to myeloid cell function and AD susceptibility. Given the druggability of LACTB and the potential for succinylcarnitine to serve as a translational biomarker, this enzyme represents a promising therapeutic target for modulation of neuroinflammation in AD.

neuroscience↗

bioRxiv2026

Aging associated RNA loss impairs the dynamics of RNA and protein condensates

Altered biomolecular condensate dynamics are increasingly implicated in age-associated neurodegenerative disorders, yet the molecular principles governing these changes remain incompletely understood. Here, we demonstrate that aged cells across diverse cellular and organismal models harbor pre-formed, viscous, and persistent stress granules (SGs), which we term alt-SGs. These persistent condensates confer protection to senescent cells under fluctuating stress conditions. Comparative analyses reveal that alt-SGs exhibit elevated RNA-binding protein (RBP)-to-RNA ratios, underscoring a shift in condensate stoichiometry. By quantifying SG composition and dynamics in live cells and in vitro, we establish that RNA concentration is a key determinant of condensate material properties, molecular composition, and dissolution capacity. Importantly, aging cells display diminished absolute RNA concentrations due to reduced RNA metabolic activity. Reactivation of RNA metabolism restores RNA/RBP ratios within SGs and alleviates aging-associated phenotypes. Together, our findings highlight RNA metabolism as a central regulator of condensate stoichiometry and function, linking metabolic decline to altered phase behavior and cellular aging. Key findingsO_LIAging and senescence have Alt-SGs with increased protein/RNA Ratio C_LIO_LIAlt-SGs are persistent after stress removal in aging C_LIO_LIAging is associated with reduced total cellular RNA C_LIO_LIReactivating RNA metabolism rescues SG phenotypes C_LIO_LIAlt-SGs are protective for senescent cell C_LI

cell biology↗

bioRxiv2026

Intracellular Delivery of Peptides and Proteins with an Engineered Membrane Translocation Domain

Antibodies and other protein therapeutics have revolutionized medicine, but their application is largely limited to extracellular targets. The lack of efficient intracellular delivery methods remains a major bottleneck. Here, we engineered a family of small ([~]90 amino acids), metabolically stable membrane translocation domains (MTDs) by modifying the loop sequences of a human fibronectin type III (FN3) domain. The most potent variant, MTD4, is highly cell-permeable and can be recombinantly fused to the N- or C-terminus of any peptide or protein, serving as a versatile "plug-and-play" vehicle. We demonstrate that MTD4 fusions efficiently deliver a wide variety of functional peptides and proteins into the cytosol and nucleus of eukaryotic cells, both in vitro and in vivo. Following systemic administration, MTD4 fusion proteins exhibit broad biodistribution and homogenous tissue penetration in mice. Importantly, MTD4 is effective at low nanomolar (nM) concentrations, making it a promising platform for addressing a vast range of intracellular and previously "undruggable" targets.

bioengineering↗

bioRxiv2025

A neuron type-specific microexon in Ank3/ankyrin-G modulates calcium activity and neuronal excitability

Recent studies have revealed many alternative exons differentially spliced across diverse neuron types in the mammalian brain, but their links to neuronal physiology remain unclear. Here we characterize a deeply conserved microexon E35a in Ank3 encoding ankyrin-G (AnkG), a multifaceted adaptor protein best known as a master organizer of the axon initial segment (AIS) and as a leading genetic risk factor for bipolar disorder. E35a is predominantly skipped in cortical glutamatergic neurons but included in cortical GABAergic neurons and cerebellar neurons, which is dictated by multiple neuronal splicing factors. In E35a-deletion mice we generated, interneurons show increased excitability and somatic Ca2+ activity, without disruption in AIS. Biochemical analyses suggest that E35a inclusion facilitates AnkG interaction with a protein complex involving inositol trisphosphate receptors (InsP3Rs) important for intracellular Ca2+ signaling. Alternative splicing therefore allows AnkG to modulate neuron type-specific excitability in addition to its ubiquitous pan-neuronal role in organizing the AIS.

neuroscience↗

bioRxiv2025

Multiomic characterization, early detection, and therapeutic targeting of myeloid sarcoma

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in [~]10% of patients, and has not yet been included in large-scale genomic studies. The critical biological changes that drive tumor evolution are unknown, its detection in asymptomatic patients remains a clinical challenge, and treatment options are limited as patients are often excluded from clinical trials, rendering it a neglected disease entity. Based on comprehensive multi-omic profiling, we demonstrate that myeloid sarcoma evolves from medullary AML with distinct sitespecific clonal evolution patterns. Additionally, we show that circulating tumor DNA sequencing can serve as a non-invasive method for molecular profiling of myeloid sarcoma, offering a novel avenue in molecular diagnostics. We characterize unique transcriptional profiles of myeloid sarcoma, reflecting immune evasion and adaptation to an extramedullary microenvironment. We provide evidence for a key role of RAS pathway activation and demonstrate in murine models of myeloid sarcoma that RAS inhibition effectively reduces tumor burden. Overall, our data highlight key differences between medullary AML and myeloid sarcoma including universal molecular evolution and RAS pathway activation as hallmarks of the disease and nominate RAS inhibition as a promising therapeutic strategy for patients with myeloid sarcoma.

cancer biology↗

bioRxiv2025

Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus

Klotho (Kl) is an anti-aging protein primarily produced in the kidney and the choroid plexus (CP, where it regulates cerebrospinal fluid composition and exerts neuroprotective effects. Here, we investigated the age-dependent consequences of a CP-specific Kl deletion on CP structure and function using mice lacking KL exclusively in CP epithelial cells (Kl{Delta}CP). In control mice, aging markedly disrupted CP architecture and cilia organization both in the lateral (LV-CP) and fourth ventricle (FV-CP). While CP-specific Kl deletion alone caused no major structural changes it induced region- and age-dependent calcification: FV-CP calcification increased in both aged and young Kl{Delta}CP mice, whereas LV-CP calcification emerged only in older Kl{Delta}CP mice. Proteomic analysis of the CP and hippocampus revealed mild molecular alterations, suggesting compensatory mechanisms that preserve structural and functional stability despite calcium dysregulation. Consistently, Kl{Delta}CP mice exhibited no significant behavioral or cognitive deficits. Overall, Kl deficiency sensitizes the CP to age-related calcification prior to overt structural decline, revealing a region-specific and functional link between Klotho, calcium imbalance, and brain aging.

neuroscience↗

bioRxiv2025

A metabolite extracted from E. coli suppresses tau aggregation

Tau aggregation is a key pathological feature of neurodegenerative diseases termed tauopathies. Identifying the various cellular factors that function to prevent tau aggregation in cells can generate key insights into how to mitigate diseases associated with protein misfolding. During an investigation into developing purification methods for the protein tau, we observed that isolates of E. coli lysate prevented human tau aggregation in vitro. Fractionation of the lysate was used to further isolate a small molecular weight (MW) inhibitory fraction containing multiple components, as determined by mass spectrometry and NMR. A putative inhibitory component, methylphosphonic acid (MePn), decreased tau amyloid formation when supplemented to in vitro aggregation assays. MePn also blocked the aggregation of expressed tau in live E. coli when supplemented to the culture media. Our findings can be directly applied to optimizing purification of recombinant tau protein and more broadly, highlight the potential of cellular metabolites to directly modulate tau amyloid formation.

biochemistry↗

bioRxiv2025

An improved epigenetic age estimation with TFMethyl Clock reveals DNA methylation changes during aging in transcription factor binding sites

Methylation-based epigenetic clocks are among the most accurate tools for predicting chronological age. Although DNA methylation (DNAm) at genomic CpG sites is linked to various regulatory mechanisms, the biological interpretability of epigenetic clocks remains surprisingly limited. One primary mechanism by which DNAm is thought to influence gene regulation is by modulating transcription factor binding activity. In this study, we examine established epigenetic clocks to assess the regulatory potential of their predictive CpGs during the aging process. Our analysis reveals that generally most CpG sites used by epigenetic clocks do not overlap known transcription factor binding sites (TFBSs), indicating that changes in TFBS dynamics may not account for prediction accuracy of these models. On the other hand, by identifying age-associated CpGs that overlap TFBSs, we identified transcription factors that may be involved in the aging process. Specifically, the TFBSs of ZBED1, NFE2, CEBPB, FOXP1, EGR1, SP1, PAX5, and MAZ were particularly enriched for age-associated CpGs, while RBPJ, NFIC, RELA, IKZF1, STAT3, and USF2 were significantly protected against methylation changes. By focusing on TFBS-associated CpGs, combined with additional feature selection and engineering steps, we developed an alternative, TFMethyl Clock model, outperforming several existing approaches. Target genes of model-selected, age-predictive CpGs are enriched in the interleukin-1b production and long- chain fatty acid metabolism pathways. In contrast, these CpGs themselves are enriched mainly at binding sites of NR2C2 TF. Furthermore, approximately three-fourths of the target genes downstream of age- predictive CpGs exhibit significant age-related changes, suggesting that our approach captures deeper insights into possible methylation-driven biological aging processes. Our findings demonstrate that incorporating regulatory loci into the design of epigenetic predictors may provide mechanistic insights into the aging process while maintaining or even improving the predictive power.

bioinformatics↗

bioRxiv2025

From Wiring to Firing: Collapse of embryonic identities and emergence of functional diversity during motor neuron maturation

Neurons born in the embryo undergo a protracted process of maturation during which time they project axons to their specific targets, integrate into circuits, refine synapses, and acquire unique electrophysiological properties. The molecular strategies that individual neuron types deploy to complete this complex process remain poorly understood. In this work, we used single nucleus multiome sequencing (RNA-seq and ATAC-seq) to track the transition from specification to functional maturation in mouse skeletal motor neurons (SMNs). Our data show that individual SMNs undergo significant transcriptional changes as they mature, but more strikingly, we find that diversity within SMNs fluctuates dramatically as the functional needs of these cells change over time. At embryonic day E15.5, when motor axons are innervating their specific muscle targets, SMNs can be subdivided into dozens of transcriptional subclusters. These embryonic subclusters represent known motor columns and pools, which utilize column- and pool-specific genes to innervate unique muscle targets. About a week later, at postnatal day 3 (P3) many column- and pool-specific genes are downregulated or become broadly expressed and SMNs coalesce on the molecular level into a more homogenous state. These neurons then undergo a second round of diversification during the first two weeks of postnatal life (P3-P13), acquiring gene expression patterns that divide them into the functionally distinct alpha, gamma, and type3 subtypes found in adults. The fluctuations in SMN diversity go hand-in-hand with changes in accessible chromatin regions and transcription factor (TF) expression. Differential ATAC-seq peaks that define embryonic diversity are lost over time while new peaks that control expression in adult subtypes are gained. TFs that are known to regulate embryonic diversity are also downregulated over time, as a separate set of TFs that likely regulate adult subtype identities are upregulated. Our work uncovers a novel maturation trajectory for postmitotic neurons where extensive spatial diversity is first acquired in the embryo to ensure proper circuit wiring; this diversity is then lost as maturing neurons re-diversify into functional identities required for proper circuit firing in postnatal life. Therefore, all aspects of a neurons identity - its morphology, circuitry, and electrophysiologically - may not be fully described by its gene expression program at adulthood, but instead is a culmination of transcriptional events that occur throughout its specification and maturation trajectory as the functional needs of the cells evolve.

neuroscience↗

bioRxiv2025

Dendritic inhibition terminates plateau potentials in CA1 pyramidal neurons

In CA1 pyramidal neurons (CA1-PYRs), plateau potentials control synaptic plasticity and the emergence of place cell identity. Here, we show that dendritic inhibition terminates plateaus in an all-or-none manner. Plateaus were initially resistant to inhibition but became increasingly susceptible to termination as they progressed. Between two distinct subtypes of dendrite-targeting interneurons, OLMNdnf generated slower postsynaptic currents that terminated plateaus more effectively than OLM2. Voltage-gated Ca2+ channels (VGCCs) were necessary for plateaus, which were prolonged by blocking small-conductance Ca2+-activated K+ channels (SK). A single-compartment model with these two conductances recapitulated core experimental findings and provided a mechanistic explanation for terminations. Plateaus arose from VGCCs maintained in the active state by sustained Ca2+ influx, a positive feedback loop that was quasi-balanced by ISK. Inhibition terminated plateaus by driving the membrane potential below a dynamic threshold to deactivate VGCCs and end the positive feedback loop. Lastly, two-photon Ca2+ imaging showed that plateaus evoke large dendritic Ca2+ transients that were graded by terminations. Overall, our results demonstrate how the feedback inhibitory circuit interacts with intrinsic cellular mechanisms to regulate plateau potentials and shape dendritic Ca2+ signals in CA1-PYRs.

neuroscience↗

bioRxiv2024

Balancing Act: A Neural Trade-Off Between Coherence and Creativity in Spontaneous Speech

Effective communication involves a delicate balance between generating novel, engaging content and maintaining a coherent narrative. The neural mechanisms underlying this balance between coherence and creativity in discourse production remain unexplored. The aim of the current study was to investigate the relationship between coherence and creativity in spontaneous speech, with a specific focus on the interaction among three key neural networks: the Default Mode Network, Multiple Demand Network, and the Semantic Control Network. To this end, we conducted a two-part analysis. At the behavioural level, we analysed speech samples produced in response to topic cues, computing measures of global coherence (indexing the degree of connectedness to the main topic) and Divergent Semantic Integration (DSI; reflecting the diversity of ideas incorporated in the narrative). Coherence and divergence in speech were negatively correlated, suggesting a trade-off between maintaining a coherent narrative structure and incorporating creative elements. At the neural level, higher global coherence was associated with greater activation in the Multiple Demand Network, emphasising its role in organising and sustaining logical flow in discourse production. In contrast, functional connectivity analyses demonstrated that higher DSI was related to greater coupling between the Default Mode and Multiple Demand Networks, suggesting that creative speech relies on a dynamic interplay between associative and executive processes. These results provide new insights into the cognitive and neural processes underpinning spontaneous speech production, highlighting the complex interplay between different brain networks in managing competing demands of being coherent and creative.

neuroscience↗

bioRxiv2024

Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro

Myeloid cells including brain-resident (microglia) and peripheral macrophages play a crucial role in various pathological conditions, including neurodegenerative disorders like Alzheimers disease (AD). They respond to disruption of tissue homeostasis associated with disease conditions by acquiring various transcriptional and functional states. Experimental investigation of these states is hampered by the lack of tools that enable accessible and robust reprogramming of human macrophages toward Alzheimers disease-relevant molecular and cellular phenotypes in vitro. In this study, we investigated the ability of a cytokine mix, including interleukin-4 (IL4), colony stimulating factor 1 (CSF1/MCSF), interleukin 34 (IL34) and transforming growth factor beta (TGF{beta}), to induce reprogramming of cultured human THP-1 macrophages. Our results indicate this treatment led to significant transcriptomic changes, driving THP-1 macrophages towards a transcriptional state reminiscent of disease-associated microglia (DAM) and lipid-associated macrophages (LAM) collectively referred to as DLAM. Transcriptome profiling revealed gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing revealed an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrated alterations in cell motility, phagocytosis, lysosomal activity, and metabolic and energetic profiles. Our findings provide insights into the cytokine-mediated reprogramming of macrophages towards disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.

immunology↗

bioRxiv2024

ProFit-1D for quantifying J-difference edited data at 3T

Reproducible and accurate fitting of the magnetic resonance spectrum is critical for estimating metabolite concentrations. We have previously developed a fitting software called ProFit-1D which was shown to fit 9.4T semi-LASER data from the human brain with high accuracy and precision. In this study, we adapted ProFit-1D to fit J-difference edited spectra acquired at a clinical field strength of 3T and to assessed its performance in simulated and in vivo data. ProFit-1D was adapted to fit J-difference edited data with alterations to the fitting range to exclude the 1.3 ppm lipid resonance, starting T2 relaxation constants, initial fit parameters, and adaptive spectral baseline determination. The accuracy of ProFit-1D was systematically evaluated on simulated GABA-edited and 2-hydroxyglutarate-edited (2HG-edited) data with different types of in vivo parameter variations and compared to that of LCModel and Gannet, two software commonly used to fit J-difference edited data. The precision of ProFit-1D was also evaluated in GABA-edited spectra acquired in vivo in the occipital cortex (OCC) and medial prefrontal cortex (mPFC) of healthy participants at 3T using subsets of averages and compared to that of LCModel and Gannet. The 2HG fit error was also evaluated for ProFit-1D in 2HG-edited spectra acquired in glioma patients and compared to that of LCModel. Overall, it was found that ProFit-1D generally produced fits with low parameter fit errors across a variety of parameter variations. GABA, glutamate plus glutamine (Glx), and 2HG levels were also more accurately estimated with ProFit-1D than with LCModel and Gannet across different spectral disturbances and simulated concentrations. ProFit-1D was found to be as precise as LCModel and more precise than Gannet in estimating GABA and Glx. 2HG fit errors were 45% lower with ProFit-1D than with LCModel. Thus, ProFit-1D was found to produce high-quality fits to J- difference edited data with high accuracy and precision.

bioengineering↗

bioRxiv2024

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects of R136S against tauopathy. One-sentence summaryThe R136S mutation on APOE3 enhances resistance to tau-related pathology and toxicity by downregulating the cGAS-STING-IFN signaling pathway.

neuroscience↗

bioRxiv2024

Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1G93A mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.

neuroscience↗