Biology subjects

Jeong, H.

Publications and source records attributed to Jeong, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

SHEST: Single-cell-level artificial intelligence from haematoxylin and eosin morphology for cell type prediction and spatial transcriptomics reconstruction

A comprehensive understanding of cancer progression requires integrating tissue morphol-ogy with spatial molecular profiles. We present SHEST, a multi-task profiling framework that leverages haematoxylin and eosin morphology to predict cellular composition and re-construct spatial gene expression at single-cell resolution. SHEST employs a quadruple-tile input capturing nuclear and contextual information, combined with a neighbourhood-informed clustering algorithm to filter ambiguous cellular signals. It comprises a shared morphological encoder with two task-specific heads: a classifier for cell type prediction and a reconstruc-tor for gene expression. Multi-task optimisation uses cross-entropy and zero-inflated negative binomial losses, specifically addressing the sparsity of spatial transcriptomic data. Evalua-tion on human lung adenocarcinoma datasets demonstrated high accuracy for the principal reciprocal constituents of the tumour-immune axis (F1: 0.97 for tumour cells and 0.91 for lym-phocytes). External validation confirmed its generalisability, revealing alveolar cells and their early neoplastic transitions. Reconstructed gene expression reproduced spatially resolved, cell-type-specific marker patterns--EPCAM in tumour cells, LTBP2 in fibroblasts, and CD3E in lymphocytes--recovering biologically coherent transcriptional architecture. SHEST also pre-served distance-dependent spatial relationships and gene-level autocorrelation, reflecting the multicellular niche structure of the tumour microenvironment. By unifying cell type iden-tification, gene expression reconstruction, and spatial mapping within a single interpretable framework, SHEST provides a synergistic and cost-efficient bridge between histopathology and spatial transcriptomics. This approach facilitates comprehensive tissue characterisation and forms a foundation for precision oncology through spatially informed, cell-level insights into tumour-immune ecosystems.

bioinformatics↗

bioRxiv2025

Telomere-to-Telomere Accurate and Gapless Korean Standard Reference Genome

We present KOREF1-G-TTAGGA, the first Telomere-to-Telomere Accurate and Gapless Genome Assembly, standing as the Korean standard reference genome. The paternal and maternal haplotypes spanned 2.91 and 3.03 Gb. Genome-wide, at least 99.15% of assembled sequences were reliably haplotype-resolved, and over 95% remained accurate even in the most error-prone loci, including centromeric satellite arrays and segmental duplications. Rare-k-mer copy-number concordance within satellite arrays held up 98.9% and 98.8% per haplotype. Bionano optical maps fully spanned all canonical rDNA arrays on the five acrocentric chromosomes. The assembly quality index (AQI) of 99.77 and 99.69 exceeded the reference-quality threshold of 90, and more than 99.99% of gene and cCRE sequence was free of structural error. Both haplotypes further showed high base-level accuracy, with consensus quality value (QV) of 81.19 and 79.03, corresponding to one error per 131 and 80 Mb. KOREF1-G-TTAGGA is among the highest-quality East Asian telomere-to-telomere assemblies. It moreover anchors a decade-spanning multi-ome reference dataset for defining individual molecular states. Together, these resources define the personal referenceome as a foundation for individual biology and precision medicine, with the assemblies, annotations, and all multi-omic data openly available at https://koreanreference.org.

genomics↗

bioRxiv2025

10,239 whole genomes with multiomic and clinical health information as the Korean population multiomic reference dataset

We present Korea10K, the largest genomic dataset of the Korean population, comprising 10,239 high-coverage whole genomes (mean depth 30x) with matched multiomic profiles and phenotype data. Korea10K achieves complete and near-complete discovery of very rare and ultra-rare alleles, respectively, at 9,000 Korean genomes. This dataset provides the high-quality population-specific imputation panel, enabling accurate inference of low-frequency variants. Admixture analyses confirm the genetic homogeneity of the Korean population, despite its diverse Y-chromosomal, mitochondrial, and HLA repertoires. This pattern reflects a long and continuous lineage history characterized by persistent internal admixture and genomic homogenization over thousands of years on the Korean peninsula. We also identified 16.8 million genomic variants that directly modify CG sites by creating or abolishing CG dinucleotides, providing the population-scale evidence of coordinated genomic-epigenomic regulatory mechanism in Koreans.

genomics↗

bioRxiv2025

Pre-existing and emergent cortical neuronal assembly sequences during learning

Neuronal assemblies -- groups of co-active neurons -- support memory consolidation and retrieval. In the hippocampus, assemblies can pre-exist learning and contribute to memory through sequential activation. Whether similar principles apply to higher cortical areas for flexible memory storage like the orbitofrontal cortex (OFC) remains unclear. Using a novel ground truth-validated clustering approach, we investigated the activity of longitudinally tracked mouse OFC neurons during cue-reward memory acquisition and maintenance. Assemblies active after learning pre-existed the learning and exhibited two distinct sequential dynamics consistent with memory consolidation or retrieval. Consolidation sequences emerged during learning, while retrieval sequences partly recruited pre-existing reward sequences. These findings demonstrate that OFC learning recruits pre-existing networks flexibly repurposed for new associations, revealing circuit motifs that may enable cortical memory storage.

neuroscience↗

bioRxiv2025

CRISPR-Induced NUT Suppression Promotes Differentiation and Enhances Trop2-Targeted Immunocytokine Response in NUT Carcinoma

NUT carcinoma (NC) is an aggressive malignancy driven by NUTM1 gene rearrangements with limited therapeutic options. Here, we show that direct suppression of NUTM1 using CRISPR/Cas9 induces squamous-like differentiation and upregulates TROP2 expression in NC cells. Building on this finding, we developed a TROP2-interferon beta (IFN-{beta}) mutein immunocytokine that selectively targets TROP2-expressing tumors. Combined NUTM1 suppression and TROP2-targeted immunotherapy synergistically enhanced cytotoxic and immune-mediated responses in vitro. Transcriptomic and spatial analyses of NC patient tumors revealed that differentiation status correlates with TROP2 expression, upregulated immune pathways, and favorable clinical outcomes. Our results suggest that overcoming differentiation blockade not only alters tumor phenotype but also creates a more immune-permissive microenvironment. These findings highlight the therapeutic potential of sequential tumor reprogramming followed by targeted immunotherapy in treating NC and propose a broader strategy for overcoming differentiation blockade in fusion-driven cancers.

cancer biology↗

bioRxiv2025

Rapid phonetic learning of Mandarin tones in adults: Daily behavioral improvement and brain activity changes

Although adults learn foreign languages more slowly than children, behavioral improvements can still emerge rapidly with training. Previous phonetic learning studies have mostly focused on pre- and post-training comparisons, leaving daily learning trajectories largely unexplored. Here, in Finnish speakers naive to tone languages, we tracked day-to-day changes in Mandarin tone perception during a short training program (1 h/day for 4 days), complemented by pre- and post-training behavioral and event-related potential (ERP) measures. Each learning session comprised exposure to Mandarin tones in continuous and isolated speech with cues, change detection and identification with feedback, and a listen-and-repeat exercise. To assess the role of co-presence, participants learned either in pairs (n = 22) or individually (n = 20). We found that discrimination and categorization speed, as well as discrimination accuracy, improved from pre-to posttest, with performance also increasing across daily training sessions. Paired learners showed higher sensitivity (d') to tone changes on the first day than individual learners, consistent with co-presence-driven attentional facilitation. At the neural level, P3a amplitude to tone changes during passive listening increased after training, reflecting enhanced automatic orienting to novel sounds at whole group level. These findings demonstrate that short-term training induces rapid behavioral gains and selective neural plasticity in adult phonetic learning, with early co-presence effects and transfer to novel speech sounds.

neuroscience↗

bioRxiv2025

Fusobacterium nucleatum produces previously unappreciated AHR-activating metabolites and promotes CRC cell proliferation via the AHR-TERT axis

Fusobacterium nucleatum (Fn) is prevalently enriched in colorectal cancer (CRC), promoting CRC progression. However, Fn-derived small molecules and their host target pathways in CRC remain largely underexplored. Here, we identify that Fn produces previously unrecognized three indole-containing metabolites, fusotrisindoline (FTIN), streptindole (STIN), and trisindoline (TIN). Using AHR reporter, CYP1A1 mRNA induction, CYP1A enzyme assay, photoaffinity AHR-ligand competition, and in silico docking, we establish that these metabolites are bona fide agonists of the aryl hydrocarbon receptor (AHR), with FTIN being the most potent AHR ligand (EC50 [~]41 nM in HepG2 cells). Genetic and pharmacological perturbations demonstrate that FTIN-activated AHR promotes proliferation, migration, and invasion in EGFR blockade-responsive CRC cell lines, such as SNU-C4, but not in EGFR blockade-resistant cell lines, such as HCT116. We show that FTIN-activated AHR signaling is critical for Fn-mediated promotion of CRC cell growth. A {Delta}tnaA mutant defective in indole production lacked FTIN/STIN/TIN production and was unable to activate AHR or enhance CRC cell growth in vitro and SNU-C4 xenograft growth in vivo. RNA-seq and follow-up functional validation identified TERT as a key downstream effector of FTIN-activated AHR signaling. FTIN upregulated TERT transcription and telomerase activity, and TERT knockdown abrogated FTIN-promoted CRC cell proliferation. FTIN production was conserved across Fn subspecies, as well as other Fusobacterium species, and detected in additional CRC- associated genera. In 30 patient pairs of CRC-matched normal colon tissues, FTIN was quantifiable in most CRC tissues and significantly enriched relative to matched normal colon tissues, whereas STIN/TIN were undetectable. Our findings reveal a metabolite-centered FTIN-AHR-TERT axis by which intratumoral bacteria, such as Fn, accelerate CRC growth and uncover FTIN as a potential biomarker in CRC.

microbiology↗

bioRxiv2025

Expression of vimentin intermediate filaments in epithelial cells promotes cell migration and cell matrix interaction in 3D

During a variety of physiological and pathological processes, such as development, wound healing, and tumor progression, epithelial cells collectively invade into their surroundings. Vimentin intermediate filaments (VIFs) are often observed to play a role in the epithelial cells located at the margins of 2D cultures. However, their role in 3D collective cell behavior remains underexplored. Here, we investigate how induced vimentin expression affects 3D multicellular architecture and mechanics in luminal breast cancer cells (MCF-7) that ordinarily express keratin intermediate filaments only. We find that vimentin expression significantly alters 3D cell cluster morphology, inducing protrusions and increasing boundary fluctuations. Furthermore, cells in vimentin-expressing clusters show enhanced, more stochastic migration. In addition, these clusters exert stronger and localized traction forces on the surrounding matrix, indicating increased cell-matrix interactions. Transcriptomic analysis corroborates these biophysical findings, revealing upregulated gene expression for cell migration and matrix adhesion, and downregulated cell-cell adhesion genes. Our results demonstrate that VIFs are critical in modulating 3D multicellular collective morphology and dynamics, promoting invasive-like behavior by enhancing cell migration and cell-matrix interactions. These results provide fundamental insights into understanding tissue morphogenesis and disease progression.

biophysics↗

bioRxiv2025

Multilayered molecular and cellular mechanisms underlying intestinal epithelial regeneration

Intestinal epithelial cells (IECs) are replenished by intestinal stem cells (ISCs) residing in the intestinal crypts and isthmus. Under homeostatic conditions, Lgr5+ crypt base columnar cells (CBCs) are considered the primary ISCs1,2. The supply of IECs, however, remains continuous even in the absence of Lgr5+ CBCs3, implying the existence of alternative ISC populations. Over the past decade, two contrasting models have emerged to explain the identities of these compensatory cells. The distinct cell population model proposes that slow-cycling, quiescent cells near the +4 position, act as reserve stem cells (rISCs)3-10. The cellular plasticity model suggests a broad spectrum of IECs can dedifferentiate into intermediate fetal-like states, thereby acquiring stemness11,12. It is unclear which of these models is correct because the signaling mechanisms governing crypt regenerative responses remain poorly understood. Here, we demonstrate that Hedgehog (Hh) signaling orchestrates intestinal regeneration following Lgr5+ CBC loss by uniquely driving the emergence of de novo Lgr5+ CBCs from non-Lgr5+ CBCs clones. This regenerative mechanism is fundamentally distinct from both classical self-renewal of existing Lgr5+ CBCs and fetal-like dedifferentiation in intestinal villi. By accelerating the cell cycle and driving clonal competition among stem cell pools, Hh signaling leaves rare dormant stem cells in the crypt and isthmus regions. These rare cells act as damage-resistant "seeds" that can promote damage recovery, thereby conferring damage resistance on the tissue as a whole. Collectively, our findings identify novel molecular and cellular mechanisms underlying ISC regeneration and suggest potential therapeutic strategies for various intestinal epithelial diseases.

cell biology↗

bioRxiv2025

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

Bipolar disorder (BD) is increasingly recognized as a disorder with both mitochondrial dysfunction and heightened inflammatory reactivity, yet their contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. Additionally, a Bioactive Flavonoid Extract (BFE) was explored as a potential therapeutic, demonstrating partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.

neuroscience↗

bioRxiv2025

Collective Transitions from Orbiting to Matrix Invasion in 3D Multicellular Spheroids

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in "mosaic" spheroids, showing a small fraction of "leader" cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

biophysics↗

bioRxiv2024

Characterization of Newly Discovered Polyester Polyurethane-degrading Methylobacterium Aquaticum Strain A1

In this study, we present Methylobacterium aquaticum A1, a novel strain capable of degrading polyester polyurethane (PE-PUR). The attachment of M. aquaticum A1 to PE-PUR and its degradation capabilities were verified using Scanning Electron Microscopy (SEM) and Fourier-Transform Infrared Spectroscopy (FT-IR). Analysis of the reference genome of M. aquaticum revealed genes encoding enzymes with potential PE-PUR degrading activity, including esterases, lipase, proteases and amidase such as tesA, pgpB, aes, aprE, lon, degQ, and gatA. An esterase activity assay using p-nitrophenyl acetate (p-NPA) showed increased ester bond-cleaving activity when M. aquaticum A1 was exposed to polyurethane diol (PU-diol), suggesting inducible enzymatic activity involved in PE-PUR degradation. These findings highlight the potential of M. aquaticum A1 as a promising biocatalyst for PE-PUR degradation. IMPORTANCEMicrobial biodegradation is increasingly recognized as a sustainable approach to addressing microplastic pollution. This study introduces M. aquaticum A1, a newly isolated strain capable of adhering to and degrading polyester polyurethane (PE-PUR), one of the most widely utilized plastics. To our knowledge, this is the first report of PE-PUR degradation by a member of the Methylobacterium genus. This paper provides a detailed characterization of M. aquaticum A1 and identifies several enzyme candidates--tesA, pgpB, aes, aprE, lon, degQ, and gatA--as potentially involved in the degradation process. Given that Methylobacterium species are known to be ecologically beneficial and inhabit diverse environments, the capacity of M. aquaticum A1 to degrade PE-PUR presents a promising strategy for mitigating microplastic pollution across a range of ecosystems.

microbiology↗

bioRxiv2024

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map ([~]3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.

genomics↗

bioRxiv2024

Structural polymorphism and diversity of human segmental duplications

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies where the majority of SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms, we identify 173.2 Mbp of duplicated sequence (47.4 Mbp not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy number when compared to non-African samples. A comparison to a resource of 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.

genomics↗

bioRxiv2024

Human Brain Aging is Associated with Dysregulation of Cell-Type Epigenetic Identity

Significant links between aging and DNA methylation are emerging from recent studies. On the one hand, DNA methylation undergoes changes with age, a process termed as epigenetic drift. On the other hand, DNA methylation serves as a readily accessible and accurate biomarker for aging. A key missing piece of information, however, is the molecular mechanisms underlying these processes, and how they are related, if any. Addressing the limitations of previous research due to the limited number of investigated CpGs and the heterogeneous nature of tissue samples, here we have examined DNA methylation of over 20 million CpGs across a broad age span in neurons and non-neuronal cells, primarily oligodendrocytes. We show that aging is a primary predictor of DNA methylation variation, surpassing the influence of factors such as sex and schizophrenia diagnosis, among others. On the genome-wide scale, epigenetic drift manifests as significant yet subtle trends that are influenced by the methylation level of individual CpGs. We reveal that CpGs that are highly differentiated between cell types are especially prone to age-associated DNA methylation alterations, leading to the divergence of epigenetic cell type identities as individuals age. On the other hand, CpGs that are included in commonly used epigenetic clocks tend to be those sites that are not highly cell type differentiated. Therefore, dysregulation of epigenetic cell-type identities and current DNA epigenetic clocks represent distinct features of age-associated DNA methylation alterations.

genetics↗

bioRxiv2024

SCO-pH: Microfluidic dynamic phenotyping platform for high-throughput screening of single cell acidification

Studies on the dynamics of single cell phenotyping have been hampered by the lack of quantitative high-throughput metabolism assays. Extracellular acidification, a prominent phenotype, yields significant insights into cellular metabolism, including tumorigenicity. Here, we develop a versatile microfluidic system for single cell optical pH analysis (SCO-pH), which compartmentalizes single cells in 140-pL droplets and immobilizes approximately 40,000 droplets in a two-dimensional array for temporal extracellular pH analysis. SCO-pH distinguishes cells undergoing hyperglycolysis induced by oligomycin A from untreated cells by monitoring their extracellular acidification. To facilitate pH sensing in each droplet, we encapsulate a cell-impermeable pH probe whose fluorescence intensities are quantified. Using this approach, we can differentiate hyperglycolytic cells and concurrently observe single cell heterogeneity in extracellular acidification dynamics. This high-throughput system will be useful in applications that require dynamic phenotyping of single cells with significant heterogeneity.

bioengineering↗

bioRxiv2024

Neuron-derived Prox1 suppresses injury-induced reprogramming of Muller glia to proliferative retinal progenitor cells

Individuals with retinal degenerative diseases face significant obstacles in restoring normal vision due to the inability to regenerate degenerated retinal cells. While retinal neurons can be regenerated from Muller glia (MG) in cold-blooded vertebrates, this regenerative ability is lacking in mammals, indicating the limited competence of mammalian MG for retinal regeneration. In this study, we elucidate the role of prospero-related homeobox 1 (Prox1) in rendering the mammalian retina incompetent for MG-derived regeneration. Prox1 accumulates in MG in the degenerating human and mouse retinas but not in those in the regenerating zebrafish retina. Strikingly, Prox1 in mouse MG originated from neighboring retinal neurons through intercellular protein transfer. Consequently, inhibition of Prox1 transfer to MG enables the reprogramming of MG into proliferative retinal progenitor cells in injured mouse retinas. Furthermore, we succeeded in regenerating retinal neurons and delaying vision loss in retinitis pigmentosa disease model in mice by adenoassociated viral gene delivery of an anti-Prox1 antibody that sequesters extracellular Prox1 in the mouse retina. Taken together, our findings highlight the therapeutic potential of anti-Prox1 therapy in restoring the regenerative potential of the mammalian retina.

developmental biology↗

bioRxiv2024

Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition of DLKs kinase domain in human patients and conditional knockout of DLK in mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative of neuronal cytoskeletal disruption. Indeed, we found that a DLK kinase domain inhibitor acutely disrupted the axonal cytoskeleton and caused vesicle aggregation in cultured dorsal root ganglion (DRG) neurons, further cautioning against this therapeutic strategy. In seeking a more precise intervention, we found that retrograde (axon-to-soma) pro-degenerative signaling requires acute, axonal palmitoylation of DLK and hypothesized that modulating this post-translational modification might be more specifically neuroprotective than cell-wide DLK inhibition. To address this possibility, we screened >28,000 compounds using a high-content imaging assay that quantitatively evaluates DLKs palmitoylation-dependent subcellular localization. Of the 33 hits that significantly altered DLK localization in non-neuronal cells, several reduced DLK retrograde signaling and protected cultured DRG neurons from DLK-dependent neurodegeneration. Mechanistically, the two most neuroprotective compounds selectively prevent stimulus-dependent palmitoylation of axonal pools of DLK, a process crucial for DLKs recruitment to axonal vesicles. In contrast, these compounds minimally impact DLK localization and signaling in healthy neurons and avoid the cytoskeletal disruption associated with direct DLK inhibition. Importantly, our hit compounds also reduce pro-degenerative retrograde signaling in vivo, suggesting that modulating DLKs palmitoylation-dependent localization could be a novel neuroprotective strategy.

neuroscience↗