Biology subjects

Hong, J. H.

Publications and source records attributed to Hong, J. H..

10 recordsLinked to original sources

bioRxiv2025

Molecular and neuropathological determinants of neuronal dysfunction in Alzheimer's disease

The biological basis of neuronal excitatory/inhibitory (E/I) imbalance in Alzheimers disease (AD) remains unclear. Using a comprehensive cohort with ante-mortem functional neuroimaging and post-mortem molecular data from the same participants, we mapped individual, whole-brain E/I imbalances through biophysical modeling. E/I ratios in regions supporting higher-order cognitive functions were significantly associated with cognitive performance and decline, with mediation by global neuropathological burden. We also observed a significant inverted U-shaped relationship between E/I ratios and neurofibrillary tangle severity, peaking at the limbic stage (Braak III-IV) in 14 brain areas, including the bilateral hippocampus and superior frontal gyrus. In addition, we identified 89 genes and 101 proteins that predict regional E/I ratios, with pathways related to synaptic signaling and immune response overrepresented. The generalizability of these molecular predictors was confirmed in two independent cohorts, achieving good classification performance for neuropathology severity and AD dementia. Lastly, the estimated E/I imbalances in AD aligned with whole-brain distributions of microglia and oligodendrocyte precursor cells, suggesting that spatial cellular organization contributes to vulnerability to neuronal dysfunction. Overall, this study provides critical insights into the cellular, molecular, and neuropathological signatures of circuit-level dysfunction in AD.

neuroscience↗

bioRxiv2025

Whole-Brain Cell-Cell Interaction Axes Explaining Tissue Vulnerability Across the Neurodegenerative Spectrum

Disrupted cell-cell communication represents a fundamental mechanism underlying neurodegeneration, yet how specific intercellular signaling patterns relate to regional brain vulnerability remains poorly understood. Here, we map whole-brain intercellular interaction networks and their spatial correspondence with tissue damage across 13 neurodegenerative conditions, including early- and late-onset Alzheimers disease, presenilin-1 mutations, clinical and pathological subtypes of frontotemporal lobar degeneration, Parkinsons disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. By integrating multiregional single-nucleus and bulk RNA-seq data with curated cell-cell interaction databases and structural MRI, we reconstruct over 1,000 whole-brain maps of ligand-receptor interactions and quantify their associations with regional atrophy patterns. Multivariate analysis identifies three dominant axes of intercellular communication that explain regional vulnerability to neurodegeneration. Notably, the first axis involves neuron-astrocyte-microglia interactions, explaining atrophy patterns shared by frontotemporal lobar degeneration and Alzheimers disease subtypes. Two complementary axes involving neurons, endothelial cells, and astrocytes explain patterns specific to mutations in PS1 and Parkinsons disease. Importantly, validation in an independent post-mortem cohort (N = 375) confirms that late-onset Alzheimers disease-associated cell-cell interactions predict observed frontal cortex atrophy. These results establish a systematic framework linking local intercellular communication networks to spatial patterns of neurodegeneration, revealing both shared and disease-specific molecular pathways that drive regional brain vulnerability and identifying cellular interaction targets for precision therapeutic interventions.

neuroscience↗

bioRxiv2025

Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans

Alzheimers disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, and effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, and post-mortem brain multi-omics data and neuroimaging to extensively characterize and translate the molecular taxonomy of AD dementia to living individuals. First, utilizing a comprehensive integration of eight complementary molecular layers from brain multi-omics data (N = 1,189), we identified three distinct molecular AD dementia subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, brain morphology, and characterized by specific cellular and molecular drivers involving immune, vascular, and oligodendrocyte precursor cells. Next, in a significant translational effort, we developed predictive models to convert these advanced brain-derived molecular profiles (AD dementia pseudotimes and subtypes) into blood-, MRI- and psychological traits-based markers. The translation results underscore both the promise of these models and the opportunities for further enhancement. Our findings enhance the understanding of AD heterogeneity, underscore the value of multi-scale molecular approaches for elucidating causal mechanisms, and lay the groundwork for the development of novel therapies in living persons that target multi-level brain molecular subtypes of AD dementia.

neuroscience↗

bioRxiv2024

Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases

Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis, yet our understanding of tumor microenvironmental (TME) characteristics associated with GCPM remain limited. Here, we analyzed intrinsic genomic alterations and transcriptomic programs predictive of GCPM in a prospective cohort of 248 patients, identifying CDH1, PIGR, and ELF3 mutations as predictors. By inspecting the spatial dynamics of the TME, we find that tumor compartment infiltration of pro-tumorigenic cell types such as inflammatory cancer-associated fibroblasts (CAFs) predict peritoneal recurrence. Next, in a cross-sectional study of 205 samples from 55 patients, distinct pathways and immune compositions in GCPM relative to liver metastases highlight the TMEs significance in transcoelomic metastases. Notably, several putative therapeutic targets exhibited distinct expression patterns between PTs and PMs. We also observed increased immune infiltration in GCPMs treated with systemic immunotherapy and intraperitoneal chemotherapy. Our findings highlight transcriptomic variations and niche reprogramming in the GCPM peritoneal environment, revealing roles of myeloid dendritic cells, effector memory CD8+ T cells, and CAFs in metastatic progression. Statement of significanceComprehensive molecular profiling of gastric cancer primary and peritoneal tumors unveils crucial insights into the distinct molecular and immune landscape of peritoneal metastases. Identifying predictive markers and therapeutic targets emphasizes the significance of tumor microenvironment alterations in guiding future therapies for gastric cancer peritoneal metastasis.

cancer biology↗

bioRxiv2023

Long-read sequencing and profiling of RNA-binding proteins reveals the pathogenic mechanism of aberrant splicing of an SCN1A poison exon in epilepsy

Pathogenic loss-of-function SCN1A variants cause a spectrum of seizure disorders. We previously identified variants in individuals with SCN1A-related epilepsy that fall in or near a poison exon (PE) in SCN1A intron 20 (20N). We hypothesized these variants lead to increased PE inclusion, which introduces a premature stop codon, and, therefore, reduced abundance of the full-length SCN1A transcript and Nav1.1 protein. We used a splicing reporter assay to interrogate PE inclusion in HEK293T cells. In addition, we used patient-specific induced pluripotent stem cells (iPSCs) differentiated into neurons to quantify 20N inclusion by long and short-read sequencing and Nav1.1 abundance by western blot. We performed RNA-antisense purification with mass spectrometry to identify RNA-binding proteins (RBPs) that could account for the aberrant PE splicing. We demonstrate that variants in/near 20N lead to increased 20N inclusion by long-read sequencing or splicing reporter assay and decreased Nav1.1 abundance. We also identified 28 RBPs that differentially interact with variant constructs compared to wild-type, including SRSF1 and HNRNPL. We propose a model whereby 20N variants disrupt RBP binding to splicing enhancers (SRSF1) and suppressors (HNRNPL), to favor PE inclusion. Overall, we demonstrate that SCN1A 20N variants cause haploinsufficiency and SCN1A-related epilepsies. This work provides insights into the complex control of RBP-mediated PE alternative splicing, with broader implications for PE discovery and identification of pathogenic PE variants in other genetic conditions.

genetics↗

bioRxiv2022

Modulation of lysosomal Cl- mediates migration and apoptosis through the TRPML1 as a lysosomal Cl- sensor

Lysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced the delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels and no changes in migratory ability. In this study, we demonstrated that the depleted chloride approach induces reformation of the lysosomal calcium pool, and subsequent dysregulated cancer progression will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.

molecular biology↗

bioRxiv2022

Adaptive Optical Coherent Raman Imaging of Axons through Mouse Cranial Bone

Coherent Raman scattering imaging has provided inherent chemical information of biomolecules without the need for any external labels.1-3 However, its working depth in deep-tissue imaging is extremely shallow because both the intrinsic scattering cross-section and image contrast are so small that even weak perturbation of the pump and Stokes beam focusing by the complex tissue causes the loss of the resolving power.4,5 Here, we propose a deep-tissue coherent Raman scattering (CRS) microscopy equipped with an advanced adaptive optics (AO) system measuring complex tissue aberration from elastic backscattering. Using this label-free AO-CRS microscopy, we demonstrate the vibrational imaging of lipid-rich substances such as myelin inside the mouse brain even through the thick and opaque cranial bones.

bioengineering↗

bioRxiv2022

Computational conjugate adaptive optics for longitudinal through-skull imaging of cortical myelin

We present a 1.3-m reflection matrix microscope and computational conjugate adaptive optics algorithm for label-free longitudinal imaging of cortical myelin through an intact mouse skull. The myelination processes of the same mice were observed from 3 to 10 postnatal weeks down to cortical layer 4 with a near-diffraction-limited resolution of 0.79 {micro}m. Our system will expedite the investigations on the role of myelination in learning, memory, and brain disorders.

neuroscience↗

bioRxiv2021

Restoring single-molecule localizations with wavefront sensing adaptive optics for deep-tissue super-resolution imaging

The specimen-induced aberration has been a major factor limiting the imaging depth of single-molecule localization microscopy (SMLM). Here, we report the application of label-free wavefront sensing adaptive optics to SMLM for deep-tissue super-resolution imaging. The proposed system measures complex tissue aberrations from intrinsic reflectance rather than fluorescence emission and physically corrects the wavefront distortion more than three-fold stronger than the previous limit. This enables us to resolve sub-diffraction morphologies of cilia and oligodendrocytes in whole intact zebrafish as well as dendritic spines in thick mouse brain tissues at the depth of up to 102 m with localization number enhancement by up to 37 times and localization precision comparable to aberration-free samples. The proposed approach can expand the application range of SMLM to intact animals that cause the loss of localization points owing to severe tissue aberrations.

cancer biology↗

bioRxiv2020

Clonal dynamics in early human embryogenesis inferred from somatic mutation

The trillions of cells that constitute the human body are developed from a fertilized egg through embryogenesis. However, cellular dynamics and developmental outcomes of embryonic cells in humans remain to be largely unknown due to the technical and ethical challenges. Here, we explored whole-genomes of 334 single-cell expanded clones and targeted deep-sequences of 379 bulk tissues obtained from various anatomical locations from seven individuals. Using the discovered 1,688,652 somatic mutations as an intrinsic barcode, we reconstructed cellular phylogenetic trees that provide novel insights into early human embryogenesis. Our findings suggest (1) endogenous mutational rate that is higher in the first cell division of life but decreases to ~1 per cell per cell division later in life, (2) universal unequal contribution of early cells into embryo proper resulting from early cellular bottlenecks that stochastically separate epiblasts from embryonic cells (3) uneven differential outcomes of early cells into three germ layers, left-right and cranio-caudal tissues, (4) emergence of a few ancestral cells that will contribute to the substantial fraction of adult blood cells, and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach additionally provides insights into the age-related mutational processes including UV-mediated mutagenesis and loss of chromosome X or Y in normal somatic cells. Taken together, this study scrutinized somatic mosaicism, clonal architecture, and cellular dynamics in human embryogenesis at an unprecedented level and provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.

genomics↗