Biology subjects

Lee, H.

Publications and source records attributed to Lee, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Relating layer fMRI signals to acoustics and intracranial neuronal activity in the human auditory cortex in a naturalistic design

Naturalistic auditory perception engages feedforward and feedback dynamics across cortical depths, yet how these are organized in the human auditory cortex has been difficult to verify noninvasively. Here, we examine depth-dependent coupling between neuronal activity and fMRI during passive music listening. Depth-specific fMRI responses were modeled using neuronal oscillation envelopes elicited by the same naturalistic stimuli from a separate group of patients under intracranial EEG monitoring. From deep toward superficial depths, the relationship between oscillatory power and fMRI responses systematically changed: alpha/beta activity (8-30 Hz) was increasingly associated with negative fMRI responses, mapping top-down feedback, while gamma band (>30 Hz) oscillations showed increasingly positive associations. Relative to a purely acoustical fMRI baseline, broadband high-frequency activity (>70 Hz), a proxy for neuronal firing, showed the strongest coupling to BOLD signals at intermediate cortical depths receiving feedforward inputs from earlier auditory pathways. Our findings reveal a spectrolaminar organization of neurovascular coupling in the human auditory cortex.

neuroscience↗

bioRxiv2026

Characterization of Nanoparticles in Suspension by Simultaneous iNTA and Fluorescence Detection with Single-Molecule Sensitivity

Quantitative knowledge of nanoparticle properties is desirable in a large number of scientific and technological applications, but measurements with a high degree of precision usually prove to be challenging. Among a range of available methodologies, optical techniques with single particle sensitivity are especially interesting because they can reveal intrinsic hetero-geneities in a fast non-invasive manner. Recently, we presented interferometric nanoparticle tracking analysis (iNTA) as a highly sensitive label-free technique that is capable of determining the size, concentration and index of refraction of different subpopulations in a suspension mixture. Here, we enhance this method with biochemical specificity through multicolor fluorescence detection at the single-molecule sensitivity limit. We benchmark the performance of the combined technique, which we name iNTA-F, by distinguishing populations of fluorescent and non-fluorescent nanoparticles of different material, size, and fluorescence intensity, with an emphasis on the characterization of lipid vesicles and biological extracellular vesicles (EVs).

biophysics↗

bioRxiv2026

Targeted sequencing of mutations via RNA-templated gap filling of oligonucleotides for single-cell RNA-seq

We describe a method for targeted sequencing of expressed mutations in single cells. The approach exploits the reverse transcriptase and nick translation activities of the Bst DNA polymerase (Full Length) from Bacillus stearothermophilus (BstFL) to perform an RNA-templated gap filling and ligation between flanking probes. Integrated with probe-based single cell RNAseq workflows, it enables simultaneous whole transcriptomic and multiplexed mutation profiling from the same cell, overcoming key limitations of mutation detection in existing scRNA-seq approaches.

molecular biology↗

bioRxiv2026

A Rapidly Excretable, ROS-Scavenging Ionizable Lipid Decouples mRNA Delivery Potency from Toxicity

The broader clinical application of mRNA therapeutics remains constrained by dose-limiting toxicities, vector-associated immunogenicity, and prolonged tissue retention of lipid nanoparticles (LNPs) in vivo. Here, we report a class of ionizable lipids incorporating a sulfur-bearing hexyl 2-hydroxyethyl sulfide (HHES) motif that decouples mRNA delivery potency from these safety liabilities through dual functionality: the sulfur moiety acts as an intrinsic reactive oxygen species scavenger to suppress oxidative stress, while undergoing oxidative conversion into hydrophilic metabolites to promote rapid systemic clearance. HHES-based LNPs demonstrated a 3.3-fold shorter hepatic half-life and 29-fold lower total hepatic exposure than MC3, while maintaining robust protein expression including functional monoclonal antibody production in vivo. Repeated dosing in non-human primates confirmed negligible systemic, hepatic, or hematological toxicity. Leveraging this safety profile, subretinal HHES LNP delivery achieved up to 57% genome editing efficiency in retinal pigment epithelium, suppressing choroidal neovascularization by [~]65% in a wet age-related macular degeneration model without structural damage or microglial activation. This dual-function design provides a generalizable framework for safe, transient, non-accumulative mRNA nanomedicines.

bioengineering↗

bioRxiv2026

Integrating Fas-mediated apoptosis with IFNγ signaling to drive tumor regression in mRNA cancer therapeutics

For mRNA-based cancer gene therapy, we engineered a membrane-bound fusion protein combining interferon-{gamma} (IFN{gamma}) with the Fas intracellular domain (FasICD) to couple local IFN{gamma} signaling with Fas-driven apoptotic tumor cell death. IFN{gamma}-FasICD was robustly expressed on the plasma membrane after mRNA transfection. In murine cancer cell lines, IFN{gamma}-FasICD mRNA reduced viability within 24 h, resulting in [~]50% cell death in MC38 cells and [~]75% in B16OVA cells, exceeding the cytotoxicity of the FasICD-deleted control (IFN{gamma}-Fas{Delta}). Mechanistically, IFN{gamma}-FasICD induced predominantly apoptotic rather than necrotic cell death. IFN{gamma}-FasICD also activated IFN{gamma} receptor signaling in both cancer and the immune cells, inducing IFN{gamma}-responsive genes in IFN{gamma}R-high B16OVA cells and triggering STAT1 phosphorylation in co-cultured splenocytes. For in vivo delivery, IFN{gamma}-FasICD mRNA was formulated in lipid nanoparticles (LNPs), enabling strong intratumoral expression that peaked at [~]3 h and persisted for more than 48 h. Repeated intratumoral injections of LNP-formulated IFN{gamma}-FasICD mRNA suppressed the growth of established B16OVA and MC38 tumors and improved survival, with [~]40% and [~]20% of mice surviving beyond 30 days, respectively. IFN{gamma}-FasICD treatment remodeled the tumor microenvironment by increasing tumor-infiltrating CD45+ cells and CD8+ T cells, while further reducing FOXP3+ regulatory T cells. Moreover, NK/NKT cells and cDC1/cDC2 populations were increased, and their activation was enhanced. In tumor-draining lymph nodes, IFN{gamma}-FasICD mRNA promoted dendritic cell migration and increased priming and differentiation of CD8+ T cells toward effector and memory phenotypes, accompanied by enhanced functional activation of IFN{gamma}-producing CD8+ T cells and highly cytotoxic NK cells in peripheral blood. Overall, our findings provide a mechanistic foundation for cytokine-death receptor fusion proteins as an in vivo antitumor strategy that can reprogram tumor cells into localized sources of both apoptotic signals and immune-activating cues.

cancer biology↗

bioRxiv2026

Multimodal Fusion of Circular Functional Data on High-resolution Neuroretinal Phenotypes

Progressive optic neuropathies, particularly glaucoma, represent a significant global health challenge, and the need for precise understanding of heterogeneous neurodegenerative phenotypes cannot be overstated. Here, we brought together two complementary sources of unstructured yet clinically relevant information about neuroretinal rim (NRR) thinning, a common clinical marker of such decay. These are based on a new dataset of fundus digital images and a corresponding dataset of optical coherence tomography, both collected from a large clinical cohort of healthy eyes. First, we represented them using a common data structure that imposed a high-resolution scale of 180 equally spaced and registered measurements on a 360{degrees} circular axis. We modeled the NRR measurements of each eye as circular curves and aligned these multimodal curves to obtain a fused NRR curve for each eye. Unsupervised clustering of these fused curves identified four clusters of eyes with structural heterogeneity, which were also found to have distinctive clinical covariates. Computation of functional derivatives revealed troughs in the curves of each cluster. Using circular statistics, we estimated the directional distributions of these troughs as potentially clinically relevant regions of NRR degeneration. A comparative study using landmark registration based on functional canonical correlation analysis demonstrated that our curve-alignment-based multimodal fusion is superior. Moreover, it improves the robustness of baseline NRR data obtained from fundus imaging.

bioinformatics↗

bioRxiv2026

Transcriptomic Integration Reveals a Conserved Inflammatory--Proliferative Paradox in Acquired Resistance to Immune Checkpoint Blockade

Acquired resistance to immune checkpoint blockade (ICB) is increasingly recognized as an active adaptive process. However, prior studies have typically focused on individual tumor models, limiting the ability to distinguish conserved mechanisms from model-specific observations. Here, we integrated four independent transcriptomic datasets of acquired ICB resistance, spanning human non-small cell lung cancer (NSCLC) biopsies, murine CT26 colorectal tumors, organoid-derived murine NSCLC tumors, and EMT6 breast cancer cells. Differential expression analysis was performed within each dataset, followed by an intersection-based consensus approach to identify reproducible resistance-associated programs. Contrary to the conventional cold tumor paradigm, acquired-resistance tumors consistently maintained interferon-{gamma} response and innate immune signaling while simultaneously activating cell-cycle programs and constitutive KRAS signaling signatures across all four models. We term this an apparent inflammatory-proliferative paradox: the persistence of IFN-{gamma}-driven inflammatory signatures, canonically associated with productive antitumor immunity, in tumors that have escaped immune control. Notably, this program was retained in immune-depleted organoid and cell-line models, supporting a tumor-cell-associated component maintained independently of the immediate immune microenvironment. Transcription factor activity inference identified a conserved regulatory backbone linking interferon-associated regulators (STAT2, IRF2) with proliferation drivers (E2F4, TFDP1) and suppression of lineage-specifying factors (HNF4A, EGR1). Integrated network analysis resolved these signals into three reinforcing modules, namely hyper-proliferative outgrowth, active inflammatory adaptation, and lineage identity loss. This architecture provides a systems-level framework for prioritizing combination strategies that simultaneously address interconnected resistance axes.

bioinformatics↗

bioRxiv2026

MitoAtlas: a Domain-Resolved Spatial Map of the HumanMitochondrial Proteome

Mitochondrial function depends on the precise sub-organellar localization and topological orientation of its proteome. However, mapping this architecture with domain-level precision across the double-membrane system has remained challenging. Here, we present MitoAtlas, a spatial systems biology resource built on SR-PL (super-resolution proximity labeling) that resolves the sub-mitochondrial architecture of 861 proteins at domain-level resolution. By deploying 42 spatially restricted APEX2 and BioID/BioID2 baits across mitochondrial compartments and cytosol in HEK293T-REx cells, we mapped 13,440 unique proximity-labeled sites. Integrating high-density spatial data with a machine-learning classification pipeline and AlphaFold structural modeling, we resolved membrane topologies for 196 transmembrane proteins and assigned sub-mitochondrial localizations to 160 previously unannotated mitochondrial proteins absent from MitoCarta3.0, including MINPP1 as an intermembrane space resident. Coupling bait-specific proximity labeling signatures with AlphaFold structure prediction and metabolite docking identified 47 protein-protein interactions, including the LETM1-Citrate Synthase complex, and 155 protein-metabolite interactions. MitoAtlas is available at mitoatlas.org as a domain-resolution spatial map of mitochondrial architecture and metabolism.

cell biology↗

bioRxiv2026

Retrosplenial cortex vulnerability links severe hypoglycemia to cognitive impairment through neuron-microglia crosstalk

Severe hypoglycemia remains a serious adverse effect of insulin therapy in individuals with diabetes and is linked to cognitive decline, yet the mechanisms by which transient metabolic stress leads to persistent neuronal dysfunction remain poorly defined. Using mouse models of acute severe hypoglycemia and integrated screening, we identified the retrosplenial cortex as a previously unrecognized brain region that is particularly vulnerable to hypoglycemia-induced neuronal damage. This injury is driven by a feedforward interaction between neuron-specific Drp1-dependent mitochondrial fission and microglial IL-1 signaling, as pharmacological or genetic targeting of either pathway suppressed the other, rescued neuronal damage, and reversed cognitive impairment. These findings identify a region-specific neuron-microglia injury circuit that links severe hypoglycemia to cognitive dysfunction and suggest a therapeutic strategy to protect brain function without compromising diabetes management.

neuroscience↗

bioRxiv2026

Parameterizing the genetic architecture under stabilizing selection

Across many complex traits, genetic variants with larger effect sizes tend to occur at lower frequencies, which is often interpreted as a signature of stabilizing selection. In statistical genetics, the so-called -model captures this relationship by assuming that effect size variance is inversely proportional to heterozygosity raised to a power 0 [<=] [<=] 1. Although empirically useful, the -model is phenomenological rather than mechanistic and lacks a direct population-genetic interpretation. In this paper, we derive an alternative to the -model based on evolutionary theory. Our approach yields a linear mixed model in which the frequency dependence of effect size emerges naturally as a function of interpretable evolutionary quantities describing mutational variance, selection intensity, and coupling between the focal and selected traits. These quantities enter through two identifiable variance components that can be estimated by restricted maximum likelihood (REML). The resulting framework links a fitness-landscape model to standard mixed-model methodology, enabling both inference on evolutionary parameters and downstream prediction by best linear unbiased prediction (BLUP). In forward simulations, the model accurately recovers the focal-trait variance and generally improves genetic prediction relative to conventional -model baselines.

genetics↗

bioRxiv2026

A novel fracture lattice in spiny mouse skin facilitates tissue autotomy and regeneration

Autotomy is a unique phenotype whereby an animal sheds a body part to escape predation1-3. The timing and location of autotomy are tightly regulated by preformed planes of weakness (aka fracture planes) which facilitate tissue loss. While autotomy is often followed by regeneration, these phenotypes are rarely reported in mammals4-9. A notable exception are spiny mice (Acomys) which exhibit skin autotomy and more remarkably, complete tissue regeneration10-14. Presently, mechanisms underlying autotomy and complete regeneration in Acomys skin remain elusive. Here, we report the discovery of a honeycomb-like fracture lattice in Acomys skin whose design directs tissue destruction but also facilitates regenerative healing. Unlike the single continuous surface of a fracture plane, this fracture lattice consists of a three-dimensional array of hexagonal units whose boundaries guide tissue breakage. Moreover, we identify collagen VI as the main constituent of the fracture lattice and find that it is distinctly arranged to initiate fracturing and propagation of skin tearing. By preconditioning the tissue for autotomy, the fracture lattice dampens the damage-induced inflammatory response but also upregulates a pro-regenerative gene signature, accelerating skin appendage regeneration. Lastly, we discovered the key role of spiny hairs in fracture lattice formation, as inhibiting their development leads to abnormal pattern formation and changes in skin fracture mechanics. Our results present a novel example of a uniquely evolved structural adaptation in mammalian skin that links tissue patterning, autotomy and regeneration. We expect that the application of a modular compartment structure to artificial skin and other organ engineering may enhance resilience to injury and facilitate efficient regeneration.

developmental biology↗

bioRxiv2026

Time-Resolved Phosphoproteomics-Guided BFS Beam Search Reveals Cell-Type-Specific EGFR Signaling Architectures and SHP2 Inhibitor-Induced Pathway Rewiring

Adaptive resistance to kinase- and phosphatase-targeted therapies is frequently driven by pharmacological rewiring of intracellular signaling networks, yet systematic computational methods for quantifying cross-condition pathway changes from phosphoproteomic data remain limited. We present an algorithmic framework for reconstructing cell-type-specific signaling pathways from time-resolved phosphoproteomic data using Breadth-First Search (BFS) combined with interaction-weight-guided Beam Search over the STRING protein-protein interaction database. The framework integrates the data-adaptive Median Absolute Deviation (MAD)-based binary-state assignment, BFS Beam Search traversal anchored to experimentally supported active nodes at zone boundaries and terminals (with STRING-inferred bridge proteins permitted as intermediate connectors), and a post-enumeration path cleaning pipeline that produces biologically interpretable, acyclic signaling routes (with edge-level validation against Human Protein Atlas-based cell-line expression data), with real-time access to the STRING REST API (v12.5), enabling network construction without local database installation. Benchmarked across five published phosphoproteomic datasets spanning three cell types (HeLa, MDA-MB-468, EGFR Flp-In HEK293T), the framework captures cell-type-specific EGFR signaling architectures and quantifies drug-induced pathway rewiring. Applied to MDA-MB-468 cells under three pharmacological conditions, SHP2 inhibition abolished PTPN11-mediated pathways and shifted first-hop effector distribution toward ERBB3 (21.5% to 25.2% of paths) and PIK3CA engagement (9.2% to 14.3% of paths), while SHP2 inhibitor washout revealed partial PTPN11 recovery with ERBB2 re-emerging as the dominant first-hop effector (30.3% of paths). This framework provides a systematic, reproducible approach for transforming time-resolved phosphoproteomic measurements into mechanistically interpretable signaling hypotheses, with direct applicability to drug resistance modeling and combination therapy design.

bioinformatics↗

bioRxiv2026

Potential of Korean Forest Tree Seed Extracts as Multifunctional Bioresources: Evaluation of Antioxidant, Anti-inflammatory, Whitening, and Anticancer Activities

Forest tree seeds are mass produced for afforestation and forest restoration programs, but are mostly underutilized beyond propagation. Here, we aimed to evaluate the antioxidant, anti-inflammatory, anticancer, and tyrosinase-inhibitory activities of seed extracts of seven economically important forest tree species in the Republic of Korea to explore their potential as multifunctional natural bioresources. The seed extracts of Alnus japonica, Chamaecyparis obtusa, Cornus kousa, Phellodendron amurense, Pinus densiflora, Prunus sargentii, and Quercus glauca were comparatively assessed using multiple in vitro assays. The results revealed clear species-dependent functional profiles rather than uniform bioactivities across species. Quercus glauca exhibited strong antioxidant activity and significant anti-inflammatory and tyrosinase-inhibitory activities, suggesting multifunctional potential, while C. obtuse presented considerable anticancer activity against several cancer cell lines. Alnus japonica exhibited the highest tyrosinase-inhibitory activity, followed by Q. glauca and C. obtuse; A. japonica extract also showed a strong antioxidant capacity. Overall, the results demonstrated that forest tree seed extracts possess diverse and complementary bioactivities, supporting their potential as underexplored multifunctional natural materials. By focusing on seed resources generated within existing afforestation systems, we highlight a sustainable approach to valorize forest-derived by-products without additional pressure on natural ecosystems. Nevertheless, as bioactivities were evaluated using crude extracts, further studies are required to identify and elucidate the active compounds and their mechanisms of action.

biochemistry↗

bioRxiv2026

Bayesian AMMI-Based Simulation of Genotype x Environment Interactions

Genotype-by-environment interaction (GEI) has been studied to identify environment-stable/favorable genotypes. The GEI simulation could help refine the inference by incorporating tangible factors such as genomic and environmental information. The Bayesian additive main effect and multiplicative interaction (Bayesian AMMI) model captures the genotype-specific responses across environments, reflecting directional relationships between genotypes and environments. Thus, we propose a Bayesian AMMI-based GEI simulation framework that utilizes high-throughput environmental covariance matrices to generate GEI effects with interpretable directional structure. To demonstrate the proposed approach, two simulated phenotypes were assessed under four levels of GEI variance. In the first simulation (Sim1), GEI effects were sampled from a multivariate normal distribution defined by the GEI matrix. In the second simulation (Sim2), GEI effects were generated by extending Sim1 with the Bayesian AMMI model. In both simulations, increasing GEI variance resulted in lower correlations of phenotypes across environments and stronger genotype-specific sensitivity to environmental variation. Across five cross-validation designs, models accounting for GEI consistently outperformed one that did not, with prediction accuracy generally decreasing as GEI variance increased. Clear distinctions between the two simulated phenotypes were evident from biplot analyses: Sim2 successfully captured environmental relatedness and genotype-specific responses, whereas such structure was absent in Sim1. These results demonstrate that the proposed Bayesian AMMI-based GEI simulation framework enables interpretable visualization of GEI and supports genomic selection strategies under complex environmental conditions.

bioinformatics↗

bioRxiv2026

Transferrin receptor 1 binds human parvovirus B19 VP1u to facilitate entry

Human parvovirus B19 (B19V) exhibits a strict tropism for erythroid progenitor cells, which is governed by the VP1 unique region (VP1u). This region mediates cell-specific uptake by interacting with an unknown cellular receptor, termed VP1uR. Proximity labeling in permissive erythroid cells identified transferrin receptor 1 (TfR1/CD71) as the predominant membrane protein associated with VP1u. VP1u constructs colocalized with TfR1 at the cell surface of erythroid cells. Incubation with anti-TfR1 antibody OKT9 abolished binding and uptake of recombinant VP1u. While OKT9 efficiently inhibited B19V uptake and infection, it did not block virus binding to host cells. Direct binding assays confirmed interaction of VP1u to human TfR1. Using cryoEM we solved the 2.4 [A] structure of the TfR1-VP1u complex, mapping the binding site and identifying the specific interactions. These findings establish TfR1 as the previously unknown receptor, VP1uR, required for B19V uptake.

microbiology↗

bioRxiv2026

The human GRK4Gamma griego minusculo 65L variant causes salt-sensitive hypertension by increasing renal SLC4A5 expression through the HDAC1 pathway

Salt-sensitive hypertension, a condition in which the blood pressure (BP) increases with an increase in salt intake, is influenced by behavioral, genetic, and environmental factors. Salt sensitivity is associated with variants of the G protein-coupled receptor kinase 4{gamma} (GRK4{gamma}) and the renal sodium bicarbonate cotransporter 2 (NBCe2), encoded by the solute carrier family 4 member 5 (SLC4A5). The R>65L variant (rs2960306) of human GRK4 (hGRK4{gamma} 65L) contributes to salt sensitivity through a signaling pathway and gene-gene interaction with SLC4A5. Global expression of GRK4{gamma} 65L in transgenic mice results in salt-sensitive hypertension, due in part to an increase in endogenous GRK4 and angiotensin type 1 receptor (AT1R) expression. Grk4 knockout (Grk4-/-) mice have decreased blood pressure and are salt-resistant. The expression of hGRK4{gamma} 65L only in the kidney of Grk4-/- mice increases BP in response to a high salt diet. The renal expression of SLC4A5 is increased in hGRK4{gamma} 65L transgenic mice, relative to mice expressing wild-type (WT) human GRK4 (hGRK4 65L), without endogenous mGrk4. Human renal proximal tubule cells (hRPTCs) endogenously expressing GRK4 WT and SLC4A5 WT, SLC4A5 variants, GRK4 65L, and both GRK4 65L and SLC4A5 variants were studied. SLC4A5 expression is increased in hRPTCs expressing GRK4 65L and in cells expressing both GRK4 65L and SLC4A5 variants compared with GRK4 WT and SLC4A5 WT. Luminal and basolateral sodium transport in hRPTCs is increased in the presence of both hGRK4 65L and SLC4A5 variants. GRK4 interacts with nuclear histone deacetylases (HDACs). Mice expressing hGRK4 65L only in the kidney have decreased expression but increased phosphorylation of HDAC1. HDAC1 expression is decreased and HDAC1 but not HDAC2 phosphorylation is increased in hRPTCs expressing both hGRK4 65L and SLC4A5 variants. The presence of hGRK4{gamma} 65L decreased HDAC1 expression but increased AT1R expression in the kidneys of mice on high salt diet. Our results show that GRK4{gamma} 65L causes salt-sensitive hypertension by increasing renal SLC4A5 and AT1R expressions by inhibiting the HDAC1 pathway.

molecular biology↗

bioRxiv2026

CDS-BART: A BART-Based Foundation Model for mRNA Sequence Analysis

Summary: Recent advancements in artificial intelligence (AI) have led to the development of foundation models that interpret mRNA as a language. Notable examples include CodonBERT, hydraRNA, EVO2, and Helix-mRNA. These models demonstrate significant potential as powerful tools for mRNA research. However, to best of our knowledge, there is currently no publicly available AI model that is both easy to use and capable of analyzing mRNA sequences up to about 4kb, a length scale typical of many therapeutic mRNAs, including those encapsulated within lipid nanoparticls (LNPs). Thus, we propose CDS-BART, a user-friendly, open-source tool that integrates SentencePiece sub-word tokenization with the denoising sequence-to-sequence training of Bidirectional and Auto-Regressive Transformers (BART). CDS-BART was pre-trained on mRNA data from nine taxonomic groups provided by the NCBI RefSeq database. This comprehensive pre-training, coupled with BARTs denoising capability, ensures effective learning of codon usage, mRNA structure, evolution, and regulation. Thus, CDS-BART can ultimately deliver robust performance across a wide range of mRNA prediction tasks. Availability and ImplementationCDS-BART is released under the MIT License. Latest code is available via Github at https://github.com/mogam-ai/CDS-BART.

bioinformatics↗

bioRxiv2026

Scn4b Modulates Huntington's Disease Phenotype Severity in vivo

Although it has been known for over 30 years that CAG trinucleotide repeat expansions in the HTT gene are the cause of Huntingtons disease (HD), it is still not understood how these mutations lead to the loss of striatal spiny projection neurons (SPNs) and other vulnerable neuronal cell types in HD. Here we show that SCN4B, a gene that is enriched in neurons that influence motor function, including striatal SPNs, modulates HD-associated phenotypes in vivo. Loss of Scn4b in wild-type mice mimics and Scn4b overexpression in an HD mouse model rescues several HD-associated phenotypes, including motor and cognitive deficits. Single nucleus RNA sequencing (snRNA-seq) analysis reveals that loss of Scn4b replicates several HD-associated gene expression signatures in the striatum. Conversely, overexpression of Scn4b rescues HD gene expression signatures and improves various SPN electrophysiological properties in HD model mice. Taken together, our results implicate loss of Scn4b expression as an important contributor to HD pathogenesis and therapeutic target in HD.

neuroscience↗