Biology subjects

Fernandez, C.

Publications and source records attributed to Fernandez, C..

At least 19 recordsLinked to original sources

bioRxiv2026

A Semantic + Neuronal Approach to Predict Pathogenic Variants in DNA Sequences

In this work, we present a machine learning model for identifying pathogenic DNA variants. The model was learned from the analysis of normal and pathogenic sequences extracted from the ClinVar database (supported by NCBI). This analysis was based on a conceptual semantic model of DNA sequences converted to peptide sequences (amino acid sequences) governed by a well-defined grammar, which allowed us to apply NLP techniques, specifically Part of Speech tagging (POS tagging). Our predictive model was built by combining two techniques: CRF (from the Markov model family), which performs the sequencing, and BiLSTM (a deep learning model) which captures the past and future content of the sequences. The training space was created with the sequences of 105 genes associated with approximately 27,000 pathogenic variants. The model was evaluated using the metrics precision, P-R and ROC curves, AUC, and confusion matrices. Its performance was also compared against five known methods for predicting pathogenic variants. The results show exceptional performance that exceeds expectations and places this new method at the state of the art for predicting pathogenic DNA sequences.

bioinformatics↗

bioRxiv2026

Adipose-Derived Extracellular Vesicles Mitigate Experimental Cutaneous Leishmaniasis Through an IL-10 Dependent Mechanism

Leishmaniasis, a neglected tropical disease caused by protozoa of the Leishmania genus, is characterized by an imbalanced immune response that promotes parasite survival while inducing tissue damage. We previously showed that adipose-derived mesenchymal stem cells (AD-MSCs) limited lesion progression in C57BL/6 mice infected with Leishmania amazonensis. In the current study, we examined whether extracellular vesicles released by AD-MSCs (AD-MSC-EVs) reproduce these therapeutic effects. AD-MSC-EVs were purified, expanded, and characterized, confirming their typical morphology and EV-associated surface markers. In vitro, treatment of infected macrophages with AD-MSC-EVs 4 hours post-infection reduced parasite load through the induction of reactive oxygen species (ROS), independent of nitric oxide (NO). However, treatment 24 hours post-infection failed to reproduce this effect. In vivo, intralesional administration of AD-MSC-EVs significantly reduced lesion size without altering parasite load, while also decreasing levels of specific IgM and IgG for Leishmania amazonensis antigens. AD-MSC-EV therapy also reduced proinflammatory cytokines production by CD4 and cytotoxicity CD8 T cells, while increasing IL-10 production by {gamma}{delta} T cells. Moreover, combined therapy with pentavalent antimonial further reduced lesion size but did not affect parasite load. Notably, AD-MSC-EVs failed to control lesions in IL-10-deficient mice, suggesting that their therapeutic effect is dependent on IL-10. In conclusion, these findings showed that AD-MSC-EVs modulated the host immune response to attenuate L. amazonensis-induced cutaneous pathology and may represent a promising adjunct or alternative therapy for cutaneous leishmaniasis. Significance StatementCutaneous leishmaniasis is a neglected tropical disease with limited therapeutic options and significant immunopathology. This study demonstrates that extracellular vesicles derived from adipose-derived mesenchymal stem cells (AD-MSC-EVs) can modulate host immune responses and reduce lesion severity in Leishmania amazonensis infection. Rather than directly eliminating parasites, AD-MSC-EVs attenuate tissue damage through IL-10 dependent immunoregulation, highlighting a novel host-directed therapeutic strategy. These findings advance understanding of EV-mediated immune modulation and support AD-MSC-EVs as a promising adjunct or alternative approach for treating cutaneous leishmaniasis and potentially other inflammatory infectious diseases.

immunology↗

bioRxiv2024

Low fidelity DNA polymerase IV accelerates genome evolution in Pseudomonas aeruginosa

Specialized DNA polymerases are crucial for bypassing lesions and facilitating various cellular processes. Despite extensive research, the mutagenic effects of these error-prone enzymes on genomes are still not fully understood. In this study, we examined the genomic instability caused by Pol IV in the bacterial pathogen Pseudomonas aeruginosa. Pol IV mutagenesis primarily involved the misincorporation of oxidized guanine nucleotides opposite template adenine. This activity led to a distinctive mutational signature, characterized by A to C transversions occurring preferentially at AT sites flanked by a 5G and/or 3C. Furthermore, Pol IV preferentially targeted specific chromosomal locations near the replication termination region and rRNA-encoding operons. Several genes associated with virulence, motility, antibiotic resistance and chemotaxis are located in these difficult-to-replicate regions, making them hotspots for Pol IV-mutagenesis. Notably, half of the mutation events catalyzed by Pol IV effectively impaired gene function. This can be attributed to the strong bias of Pol IV for mutating specific codons with its preferred sequence contexts, leading to substitutions primarily to the unreactive Ala and Gly residues. Remarkably, mutation signatures identified for Pol IV were also present in genomes from clinical isolates of P. aeruginosa, providing compelling evidence for its role in genetic diversification during pathogen adaptation.

genomics↗

bioRxiv2024

Structural basis of dual BACH1 regulation by SCFFBXO22 and SCFFBXL17

BTB and CNC homolog 1 (BACH1) is a master transcriptional regulator of the cellular oxidative stress response and pro-metastatic oncogene. Post-translational stability of BACH1 is tightly regulated by distinct F-box ubiquitin ligases, including SCFFBXO22 and SCFFBXL17. However, the molecular details have been elusive. Here, we reveal a structural switch in FBXO22 that controls the recognition of a three-dimensional degron in the BACH1 BTB domain, thus explaining its specificity for dimeric BACH1. We describe how cancer-associated mutations in FBXO22 modulate binding and ubiquitylation of BACH1. Further, we reveal that cancer-related mutations or cysteine-modifications destabilize the BTB domain and redirect BACH1 to FBXL17, where it is recognized as a monomer. This explains how complementary ligases post-translationally regulate BACH1 depending on the state of its BTB domain. Our findings provide mechanistic insights into the regulation of the oxidative stress response and may spur therapeutic strategies to targeting oxidative stress-related disorders and metastatic cancers.

biophysics↗

bioRxiv2024

Nuclear RNAi Modulates Influenza A Virus Infectivity By Downregulating Type-I Interferon Response

The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We reveal that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71, a proposed AGO2 E3 ligase, and type-I interferon-pathway genes for silencing. Accordingly, Tp53-/- mice do not accumulate nuclear AGO2 and demonstrate decreased susceptibility to IAV infection. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. Furthermore, the FDA approved drug arsenic trioxide, which prevents p53 tetramerization and nuclear translocation, increases interferon response and decreases viral replication in vitro and in a mouse model in vivo. Our data indicates that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.

biochemistry↗

bioRxiv2023

Loss of Lamin A leads to the nuclear translocation of AGO2 and compromised RNA interference

In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event; however, in the last decade, a growing number of reports convincingly show the nuclear localization of the Argonaute (AGO) proteins. Nevertheless, the extent of nuclear RNAi and its implication in biological mechanisms remain to be elucidated. We found that reduced Lamin A levels significantly induce nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 cells, evident by changes in cell morphology, increased cell proliferation, and oncogenic miRNA expression. Furthermore, in SHSY5Y cells, AGO fPAR-CLIP in Lamin A KO cells revealed significantly reduced activity of RNAi. Further exploration of the nuclear AGO interactome by mass spectrometry indicated that AGO2 is in complex with FAM120A, an RNA-binding protein and known interactor of AGO2. By performing FAM120A fPAR-CLIP, we discovered that FAM120A co-binds AGO targets and that this competition reduces the activity of RNAi. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, RNAi impairment, and selective upregulation of oncogenic miRNAs, facilitating cancer cell proliferation.

biochemistry↗

bioRxiv2023

Impact of Phosphorylation on alpha-Synuclein Structural Determinants

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human -synuclein (AS), a key player in Parkinsons disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations suggest that phosphorylation does not impact the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS contains {beta}-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the non-physiological (non-acetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data, with the caveat of the observed limitations of the force field for the phosphorylated moiety. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/531864v4_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@108c32dorg.highwire.dtl.DTLVardef@45e5d7org.highwire.dtl.DTLVardef@f49cf6org.highwire.dtl.DTLVardef@16ceb61_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Leaf metabolic traits reveal hidden dimensions of plant form and function

The plant metabolome encompasses the biochemical mechanisms through which evolutionary and ecological processes shape plant form and function1,2. However, while the metabolome should thus be an important component of plant life-history variation3, we know little about how it varies across the plant kingdom. Here, we use the plant functional trait concept4 - a powerful framework for describing plant form and function5-7 - to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five discriminant metabolic functional traits reveals that plants vary along two major axes of leaf metabolic specialization - a leaf chemical defense spectrum and an expression of leaf longevity. These axes are qualitatively consistent for tropical and temperate species, with many trait combinations being viable. However, axes of leaf metabolic specialization vary orthogonally to life-history strategies described by widely used functional traits5-7, while being at least equally important to them. Our findings question classical trait6 and plant defense8 theory that predicts relationships between the leaf chemical phenotype, plant productivity, and pace of life. Moreover, we show that metabolic functional traits describe unique dimensions of plant life-history variation that are complementary to, and independent from, those captured by existing plant functional traits.

ecology↗

bioRxiv2022

Representational integration and differentiation in the human hippocampus following goal-directed navigation

As we learn, dynamic memory processes build structured knowledge across our experiences. Such knowledge enables the formation of internal models of the world that we use to plan, make decisions, and act. Recent theorizing posits that mnemonic mechanisms of differentiation and integration - which at one level may seem to be at odds - both contribute to the emergence of structured knowledge. We tested this possibility using fMRI as human participants learned to navigate within local and global virtual environments over the course of three days. Pattern similarity analyses on entorhinal cortex, hippocampus, and ventromedial prefrontal cortex patterns revealed evidence that differentiation and integration work concurrently to build local and global environmental representations, and that variability in integration relates to differences in navigation efficiency. These results offer new insights into the neural machinery and the underlying mechanisms that translate experiences into structured knowledge that allows us to navigate to achieve goals.

neuroscience↗

bioRxiv2022

CRISPRcleanR WebApp: an interactive web application for processing genome-wide pooled CRISPR-Cas9 viability screen

A limitation of pooled CRISPR-Cas9 viability screens is the high false-positive rate in detecting essential genes arising from copy number-amplified (CNA) regions of the genome. To solve this issue, we developed CRISPRcleanR: a computational method implemented as R/python package and in a dockerized version. CRISPRcleanR detects and corrects biased responses to CRISPR-Cas9 targeting in an unsupervised fashion, accurately reducing false-positive signals, while maintaining sensitivity in identifying relevant genetic dependencies. Here, we present CRISPRcleanRWebApp, a web-based application enabling access to CRISPRcleanR through an intuitive graphical web-interface. CRISPRcleanRWebApp removes the complexity of low-level R/python-language user interactions; it provides a user-friendly access to a complete analytical pipeline, not requiring any data pre-processing, and generating gene-level summaries of essentiality with associated statistical scores; it offers a range of interactively explorable plots, while supporting a wider range of CRISPR guide RNAs libraries with respect to the original package. CRISPRcleanRWebApp is freely available at: https://crisprcleanr-webapp.fht.org/. HighlightsO_LICRISPR-Cas9 screens are widely used for the identification of cancer dependencies C_LIO_LIIn such screens, false-positives arise from targeting copy number amplified genes C_LIO_LICRISPRcleanR corrects this bias in an unsupervised fashion C_LIO_LICRISPRcleanRWebApp is a web user-friendly front-end for CRISPRcleanR C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/483924v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@739480org.highwire.dtl.DTLVardef@1a6c0aorg.highwire.dtl.DTLVardef@ab2b8eorg.highwire.dtl.DTLVardef@1b8a623_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2021

Quantitative imaging of transcription in living Drosophila embryos reveals the impact of core promoter motifs on promoter state dynamics

Genes are expressed in stochastic transcriptional bursts linked to alternating active and inactive promoter states. A major challenge in transcription is understanding how promoter composition dictates bursting, particularly in multicellular organisms. We investigate two key Drosophila developmental promoter motifs, the TATA box (TATA) and the Initiator (INR). Using live imaging in Drosophila embryos and new computational methods, we demonstrate that bursting occurs on multiple timescales ranging from seconds to minutes. TATA-containing promoters and INR-containing promoters exhibit distinct dynamics, with one or two separate rate-limiting steps respectively. A TATA box is associated with long active states, high rates of polymerase initiation, and short-lived, infrequent inactive states. In contrast, the INR motif leads to two inactive states, one of which relates to promoter-proximal polymerase pausing. Surprisingly, the model suggests pausing is not obligatory, but occurs stochastically for a subset of polymerases. Overall, our results provide a rationale for promoter switching during zygotic genome activation.

molecular biology↗

bioRxiv2020

Biotic and abiotic factors shaping the genome of cockle (Cerastoderma edule) in the Northeast Atlantic: a baseline for sustainable management of its wild resources

Knowledge on how environmental factors shape the genome of marine species is crucial for sustainable management of fisheries and wild populations. The edible cockle (Cerastoderma edule) is a marine bivalve distributed along the Northeast Atlantic coast of Europe and is an important resource from both commercial and ecological perspectives. We performed a population genomics screening using 2b-RAD genotyping on 9,309 SNPs localised in the cockles genome on a sample of 536 specimens pertaining to 14 beds in the Northeast Atlantic to ascertain its genetic structure regarding environmental variation. Larval dispersal modelling considering species behaviour and interannual variability in ocean conditions was carried out, as an essential background to compare genetic information with. Cockle populations in the Northeast Atlantic were shown to be panmictic and displayed low but significant geographical differentiation across populations (FST = 0.0240; P < 0.001), albeit not across generations. We identified 441 outlier SNPs related to divergent selection, sea surface temperature being the main environmental driver following a latitudinal axis. Two main genetic groups were identified, northwards and southwards of French Brittany, in accordance with our modelling, which demonstrated a barrier for larval dispersal linked to the Ushant front. Further genetic subdivision was observed using outlier loci and considering larval behaviour. The northern group was divided into the Irish/Celtic Seas and the English Channel/North Sea, while the southern group was divided into three subgroups. This information represents the baseline for management of cockles, designing conservation strategies, founding broodstock for depleted beds, and producing suitable seed for aquaculture production.

genomics↗

bioRxiv2020

A comprehensive analysis of vomeronasal organ transcriptome reveals variable gene expression depending on age and function in rabbits

The vomeronasal organ (VNO) is a chemosensory organ specialized in the detection of pheromones and consequently the regulation of behavioural responses mostly related to reproduction. VNO shows a broad variation on its organization, functionality and gene expression in vertebrates, and although the species analyzed to date have shown very specific features, its expression patterns have only been well-characterized in mice. Despite rabbits represent a model of chemocommunication, unfortunately no genomic studies have been performed on VNO of this species to date. The capacity of VNO to detect a great variety of different stimuli suggests a large number of genes with complex organization to support this function. Here we provide the first comprehensive gene expression analysis of the rabbit VNO through RNA-seq across different sexual maturation stages. We characterized the VNO transcriptome, updating the number of the two main vomeronasal receptor (VR) families, 129 V1R and 70 V2R. Among others, the expression of transient receptor potential channel 2 (TRPC2), a crucial cation channel generating electrical responses to sensory stimulation in vomeronasal neurons, along with the specific expression of some fomyl-peptide receptors and H2-Mv genes, both known to have specific roles in the VNO, revealed a the particular gene expression repertoire of this organ, but also its singularity in rabbits. Moreover, juvenile and adult VNO transcriptome showed consistent differences, which may indicate that these receptors are tuned to fulfill specific functions depending on maturation age. We also identified VNO-specific genes, including most VR and TRPC2, thus confirming their functional association with the VNO. Overall, these results represent the genomic baseline for future investigations which seek to understand the genetic basis of behavioural responses canalized through the VNO. HIGHLIGHTSO_LIFirst description of the rabbit vomeronasal organ (VNO) transcriptome C_LIO_LIVNO contains a unique gene repertoire depending on the species C_LIO_LIHigh fluctuation of the VNO gene expression reveals changes dependent on age and specific functions C_LIO_LIMost vomeronasal-receptors (VR) and transient receptor potential channel 2 (TRPC2) genes are VNO-specific C_LIO_LIReproduction-related genes shows a wide expression pattern C_LI

genomics↗

bioRxiv2020

Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.

genetics↗

bioRxiv2019

Intercellular transmission of a bacterial cytotoxic prion-like protein in mammalian cells

RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent to mitochondria impairment in human cells affected by neurodegeneration. To fulfil all the features of a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1(WT) and assayed its response to co-incubation with in vitro assembled RepA-WH1(A31V) amyloid fibres. In parallel, cells releasing RepA-WH1(A31V) aggregates were co-cultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibres and the extracellular RepA-WH1(A31V) aggregates induce, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells point to alterations in mitochondria, protein quality triage, signalling and intracellular traffic.\n\nSummary blurbThe horizontal, cell-to-cell spread of a bacterial prion-like protein is shown for the first time in mammalian cells. Amyloid cross-aggregation of distinct variants, and their associated toxicities, follow the same trend found in bacteria, underlining the universality of prion biology.

microbiology↗

bioRxiv2019

Conformational Priming of RepA-WH1 for Functional Amyloid Conversion Detected by NMR Spectroscopy

How proteins with a stable globular fold acquire the amyloid state is still largely unknown. RepA is a versatile plasmidic DNA binding protein, functional either as a transcriptional repressor or as an initiator or inhibitor of DNA replication, the latter through the assembly of an amyloidogenic oligomer. Its N-terminal domain (WH1) is responsible for discrimination between these functional abilities by undergoing hitherto unknown structural changes. Furthermore, when expressed alone, RepA-WH1 behaves as a synthetic prion-like protein causing an amyloid proteinopathy in bacteria. RepA-WH1 is a stable dimer whose conformational dynamics had not been explored. Here we have studied it through NMR {1H}-15N relaxation and H/D exchange kinetics measurements. The N- and the C- terminal -helices, which lock the WH1 fold in each subunit of the dimer, as well as an internal amyloidogenic loop, show reduced stability and are partially unfolded in solution. S4-indigo, a small molecule ligand known to interfere with the amyloid assembly of RepA-WH1, binds to and tethers the N-terminal -helix and a {beta}-hairpin that is involved in dimerization, thus providing evidence for a priming role of fraying ends and dimerization switches in the amyloidogenesis of folded proteins.

biochemistry↗

bioRxiv2019

Resting networks and personality predict attack speed in social spiders

Groups of social predators capture large prey items collectively, and their social interaction patterns may impact how quickly they can respond to time-sensitive predation opportunities. We investigated whether various organizational levels of resting interactions (individual, sub-group, group), observed at different intervals leading up to a collective prey attack, impacted the predation speed of colonies of the social spider Stegodyphus dumicola. We found that in adult spiders overall group connectivity (average degree) increased group attack speed. However, this effect was detected only immediately before the predation event; connectivity two and four days before prey capture had little impact on the collective dynamics. Significantly, lower social proximity of the groups boldest individual to other group members (closeness centrality) immediately prior and two days before prey capture was associated with faster attack speeds. These results suggest that for adult spiders, the long-lasting effects of the boldest individual on the groups attack dynamics are mediated by its role in the social network, and not only by its boldness. This suggests that behavioural traits and social network relationships should be considered together when defining keystone individuals in some contexts. By contrast, for subadult spiders, while the group maximum boldness was negatively correlated with latency to attack, no significant resting network predictors of latency to attack were found. Thus, separate behavioural mechanisms might play distinctive roles in determining collective outcomes at different developmental stages, timescales, and levels of social organization.\n\nSignificance statementCertain animals in a group, such as leaders, may have a more important role than other group members in determining their collective behavior. Often these individuals are defined by their behavioral attributes, for example, being bolder than others. We show that in social spiders both the behavioral traits of the influential individual, and its interactions with other group members, shape its role in affecting how quickly the group collectively attacks prey.

animal behavior and cognition↗

bioRxiv2018

Homeostatic versus pathological functions of Dual Leucine Zipper Kinase in the adult mouse brain

Dual Leucine Zipper Kinase (DLK, Map3k12), is an injury-induced axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). DLK is generally considered to be inactive in healthy neurons until induced by injury. However we report that DLK in the cerebellum appears constitutively active and drives nuclear p-c-Jun in cerebellar granule neurons in the absence of injury. In contrast the adult hippocampus expresses similar levels of apparently constitutively active DLK, but p-c-Jun is lower and does not accumulate in the nucleus. Injury is required there for p-c-jun nuclear expression, because in the rTg4510 model of tauopathy, where there is extensive hippocampal pathology, nuclear p-c-Jun is induced in a DLK-dependent manner. This context-specific regulation of DLK signaling could relate to availability of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1) whereas the hippocampus contains more JIP-3 and Plenty of SH3 (POSH). To understand how DLK signaling differs between the hippocampus and cerebellum, we selectively blocked DLK and measured changes in protein and mRNA expression. In the cerebellum, p-c-Jun levels correlated with synaptophysin, suggesting a link between DLK activity and synaptic maintenance. In rTg4510 mice, hippocampal p-c-Jun instead correlated with markers of neuronal injury and gliosis (Iba1 and GFAP). RNA sequencing revealed that in both brain regions DLK inhibition reduced expression of JNK/c-Jun pathway components and a novel set of co-regulated genes. In the cerebellum, Jun mRNA levels were co-regulated with genes mapping to metabolic pathways, while in the rTg4510 hippocampus, Jun-correlated mRNAs correspond primarily to neuroinflammation. These data suggest that in the uninjured cerebellum, DLK/p-c-Jun signaling is linked to synaptic regulation, but in the hippocampus, pathologically activated DLK/p-c-Jun signaling regulates genes associated with the injury response.

neuroscience↗