Biology subjects

Moctezuma, F. G. R.

Publications and source records attributed to Moctezuma, F. G. R..

5 recordsLinked to original sources

bioRxiv2026

Neuronal p38α knockout protects against neurological consequences following repetitive mild traumatic brain injury

Mild traumatic brain injuries (mTBI) can substantially impact quality of life, and repetitive mTBIs (rmTBI) can amplify injury effects compared to a single injury. However, effective clinical treatments remain elusive, largely due to an incomplete understanding of the underlying injury mechanisms. Neuroinflammation has emerged as a key contributor to worse functional outcomes after mTBI/rmTBI. While microglia are traditionally viewed as primary mediators of post-injury inflammation, accumulating evidence suggests neurons play an immunomodulatory role in initiating the rmTBI inflammatory cascade through activation of intracellular proinflammatory pathways like p38 MAPK and secretion of cytokines that, in turn, stimulate microglial activation. Here, we tested whether inducible neuronal p38 knockout protects against functional, immune, and cerebrovascular consequences of a weight-drop closed head injury model of rmTBI. A battery of functional assays was conducted 4 weeks post-injury, and tissues were collected at both 4 hours and 4 weeks following final CHI. In males, neuronal p38 knockout protected against injury-induced depressive-like behavior, hyperactivity, synaptic loss, microglial reactivity, cytokine upregulation, and reduction in cerebral blood flow. In females, neuronal p38 knockout protected against risk-taking behavior and partially protected against cytokine upregulation but had limited effect on microglial reactivity and cerebral blood flow. Together, these findings identify neuronal p38 as a sex-dependent driver of rmTBI-associated neurological consequences, and they support neuronal p38-immune signaling as a mechanistically relevant therapeutic target for future studies.

neuroscience↗

bioRxiv2025

MetaboFM: A Foundation Model for Spatial Metabolomics

Mass spectrometry imaging (MSI) provides molecularly resolved maps of metabolites and lipids across tissues, yet the lack of large-scale, unified representation learning frameworks limits its potential for generalization and downstream analysis. Here, we introduce MetaboFM, a foundation model for spatial metabolomics that consolidates thousands of public MSI datasets into standardized spatial-spectral tensors and extracts transferable embeddings using pretrained Vision Transformers. We curated and standardized around 4000 publicly available MSI datasets from the METASPACE repository, spanning multiple organisms, tissue types, ionization modes, and instruments. Across six metadata prediction tasks--encompassing organism, ionization polarity, tissue type, condition, analyzer type, and ionization source embeddings from pretrained MetaboFM encoders achieved a mean macro-F1 of 0.74 and accuracy of 0.80 with linear probes, demonstrating substantially higher discriminative power than classical principal component analysis (PCA) or randomly initialized baselines by over 20 percentage points. To interpret the learned representations, we mapped embedding directions back to the m/z domain, revealing distinct spectral regions that drive class separation across tissues, conditions, and ionization sources. A multimodal visual question answering (VQA) extension further links MSI embeddings with natural-language queries through a cross-attention fusion module, attaining an average macro-F1 of 0.61 {+/-} 0.05 across tasks. Finally, an interactive Gradio interface enables users to visualize MSI patches and query sample metadata in free-form language. Together, MetaboFM establishes a scalable foundation model paradigm for MSI, unifying representation learning, spectral interpretability, and multimodal interaction within a single framework for spatial metabolomics.

bioinformatics↗

bioRxiv2025

Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation

Manganese is an essential trace element required for various biological functions, but in excess is neurotoxic and leads to significant health concerns. The mechanisms underlying manganese neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, and neuroinflammation. Here, we present a novel manganese-dependent mechanism linking mitochondrial dysfunction to neuroinflammation. We found that manganese disruption of the mitochondrial transcriptome processing results in the accumulation of double stranded RNA (dsRNA). This dsRNA is released into the cytoplasm, where it activates the cytosolic sensor MDA5, triggering type I interferon responses and inflammatory cytokine production. This mechanism is evident in 100 day human cerebral organoids, where manganese-increased mitochondrial dsRNA and induced inflammatory responses in mature astrocytes. Similarly, we observed an increase in mitochondrial dsRNA content, the activation of an inflammatory transcriptome and the production of cytokines in female and male mouse brains carrying mutations in the Slc30a10 gene, a model for human hypermanganesemia with dystonia 1 disorder. These findings highlight a previously unrecognized role for mitochondrial dsRNA in manganese-induced neuroinflammation and provide insights into the molecular pathogenesis of manganism. We propose that this mitochondrial dsRNA-induced inflammatory pathway could be active in other neurological diseases caused by environmental or genetic factors. Significance StatementEnvironmental exposures and genetic defects that perturb manganese homeostasis are an underappreciated cause of neurodegeneration and neuroinflammation. We describe a new paradigm for inducible neuroinflammation, where manganese disruption of mitochondrial transcriptome processing leads to the accumulation of mitochondrial double-stranded RNA (dsRNA), which activate antiviral responses in the cytoplasm driving type I interferon dependent inflammation. This manganese-dsRNA axis is induced in cell lines in vitro and a subpopulation of mature astrocytes in exposed human cerebral organoids. Brain cortex of mice deficient in the manganese efflux transporter Slc30a10, a genetic model of chronic manganese accumulation, show dsRNA accumulation, and up-regulation of type I interferon response and astrogliosis markers, supporting a role for this pathway in neurotoxicity and parkinsonism.

neuroscience↗

bioRxiv2024

Super Resolved Single-Cell Spatial Metabolomics from Multimodal Mass Spectrometry Imaging guided by Imaging Mass Cytometry

Mass spectrometry imaging (MSI) is a powerful technique for spatially resolved analysis of metabolites and other biomolecules within biological tissues. However, the inherent low spatial resolution of MSI often limits its ability to provide detailed cellular-level information. To address this limitation, we propose a guided super-resolution (GSR) approach that leverages high-resolution Imaging Mass Cytometry (IMC) images to enhance the spatial resolution of low-resolution MSI data. By using these detailed IMC images as guides, we improve the resolution of MSI images, creating high-resolution metabolite maps. This enhancement facilitates more precise analysis of cellular structures and tissue architectures, providing deeper insights into super-resolved spatial metabolomics at the single-cell level.

systems biology↗

bioRxiv2024

Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration

Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that was associated with a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7aflx/Y :: Vil1Cre/+ mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency. SignificanceO_LICopper deficiency is present in rare conditions such as Menkes disease and CTR1 deficiency and in more common diseases like Alzheimers. The mechanisms of resilience and ultimate susceptibility to copper deficiency and associated pathology in the brain remain unknown. C_LIO_LIWe demonstrate that in a human cell line, Drosophila, and the mouse cerebellum, copper-deficient neuronal cells exhibit increased protein synthesis through mTORC1 activation and decreased PERK (EIF2AK3) activity. C_LIO_LIUpregulation of protein synthesis facilitates resilience of neuronal cells to copper deficiency, including partial restoration of dendritic arborization. Our findings offer a new framework for understanding copper deficiency-related pathology in neurological disorders. C_LI

neuroscience↗