Biology subjects

Park, A. S.

Publications and source records attributed to Park, A. S..

7 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Transcriptomic Dissection Uncovers Age-Dependent Deceleration of Esophageal Cell Differentiation

Precise orchestration of stem and progenitor cells is essential for tissue homeostasis and regeneration but becomes dysregulated during aging. Despite the known markers, the age-related dynamics of esophageal epithelial cell lineages remain unclear. Using single-cell single cell transcriptomics, we analyzed human esophageal epithelia across different age groups. We identified two stem cell populations: quiescent (qeSCs) and proliferative (peSCs) esophageal stem cells. qeSCs from young donors showed higher WNT10A expression and Wnt signaling activity. Analysis of cell lineage trajectories combined with cell plastic potentials showed stronger connectivity between peSCs and differentiated cells in younger tissues, indicating more efficient and rapid epithelial turnover and homeostatic maintenance. Cell-cell interaction analysis further demonstrated that NOTCH signaling is more prominent within peSCs and qeSCs in younger esophagi, whereas in older tissues, NOTCH activity is preferentially retained in differentiated cells. Additionally, the inflammatory signaling, Interleukin-1 pathway, is more active in younger esophagi but is largely restricted to differentiated cells. Our findings suggest that age-related decline in esophageal homeostasis is primarily driven by impaired differentiation dynamics rather than by alterations in stem cell self-renewal capacity.

cell biology↗

bioRxiv2026

Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes

Genomic copy number variations, such as the 22q11.2 microdeletion syndrome, cause pleiotropic disorders that affect diverse organ systems and disrupt neurodevelopment. Deletions of the 22q11.2 locus reduce the dosage of up to 46 protein coding genes, raising questions about the identity of haploinsufficient genes and their genetic interactions contributing to 22q11.2 phenotypes. Here, we dissect functional and molecular relationships between two genes encoded within the 22q11.2 locus: the mitochondrial ribosomal protein gene MRPL40 and the mitochondrial citrate transporter SLC25A1. We show that a MRPL40 null mutation disrupts mitochondrial translation, impairs respiration, and affects multiple components of the SLC25A1 interactome including factors required for lipid metabolism, mitochondrial ribosome subunits, and the mitochondrial RNA processing machinery. In silico coessentiality network analysis revealed correlated and anticorrelated fitness interactions linking MRPL40 and SLC25A1 to mitochondrial translation, intermediate carbon metabolism, and interferon signaling. We determined that Mrpl40-null mutations are embryonic lethal in mice, but Mrpl40-/+ mice are viable and displayed embryonic cardiac development and adult behavioral phenotypes. Similarly, Slc25a1+/- animals showed embryonic cardiac developmental defects but lacked the adult behavioral phenotypes observed in Mrpl40-/+ mice. Surprisingly, transheterozygotic Slc25a1+/-;Mrpl40-/+ mice suppressed or mitigated cardiac development, behavioral, and brain transcriptome phenotypes observed in single heterozygotic animals. These results reveal that MRPL40 and SLC25A1 are haploinsufficient genes within the 22q11.2 locus that genetically and biochemically interact to define tissue development and physiology. Our findings provide a framework for understanding the complexity and type of gene dosage interactions within the 22q11.2 deletion syndrome locus.

neuroscience↗

bioRxiv2025

Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons

Huntingtons disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications (PTMs), such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or Ctrl-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD- iNs, suggesting a compensatory mechanism - a pattern also observed in human post mortem cortical HD tissue. Additionally, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology and thus site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.

neuroscience↗

bioRxiv2025

POMPOMS: Crosslinked biomolecular condensates as a versatile platform for multifunctional protein microparticles.

Protein-based microparticles are promising materials for applications such as biocatalysis and biomolecular capture, yet their fabrication by existing techniques remains challenging due to protein denaturation or lack of spatial control. Here, we present a method for synthesizing microscale protein-based materials by chemically crosslinking biomolecular condensates. Leveraging the liquid-liquid phase separation behavior of intrinsically disordered RGG domains, we sequestered RGG-tagged fusion proteins into droplets, then we solidified them into porous microparticles using the homobifunctional, amine-reactive crosslinker BS3. By modulating protein concentration and condensate coalescence, we controlled microparticle size from <1 to >40 {micro}m. We then demonstrated three encodable functionalities: We used the SpyCatcher/SpyTag system to capture cargo proteins, we crosslinked core-shell condensates to generate microparticles with controlled spatial organization, and we immobilized a thermostable alcohol dehydrogenase with 31% retained enzymatic activity. These POMPOMS (protein-based, self-organized microparticles of multifunctional significance) represent a sustainable, tunable platform for versatile protein-based materials.

biochemistry↗

bioRxiv2024

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh+ neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh+ neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naive female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

neuroscience↗

bioRxiv2022

Efficacy of Non-invasive Brain Stimulation on Vision: A Systematic Review and Meta-analysis

ObjectiveMultiple studies have explored the use of non-invasive brain stimulation (NIBS) to enhance visual function. These studies vary in sample size, outcome measures, and NIBS methodology. We conducted a systematic review and meta-analyses to assess the effects of NIBS on visual functions in human participants with normal vision. MethodsWe followed the PRISMA guidelines, and a review protocol was registered with PROSPERO before study commencement (CRD42021255882). We searched Embase, Medline, PsychInfo, PubMed, OpenGrey and Web of Science using relevant keywords. The search covered the period from 1st January 2000 until 1st September 2021. Comprehensive meta-analysis (CMA) software was used for quantitative analysis. ResultsForty-nine studies were included, of which 19 were included in a meta-analysis (38.8%). Meta-analysis indicated acute (Hedgess g=0.232, 95% CI: 0.023-0.442, p=0.029) and aftereffects (0.590, 95% CI: 0.182-0.998, p=0.005) of transcranial electrical stimulation (tES, including three different stimulation protocols) on contrast sensitivity. Visual evoked potential (VEP) amplitudes were significantly enhanced immediately after tES (0.383, 95% CI: 0.110-0.665, p=0.006). Both tES (0.563, 95% CI: 0.230 to 0.896, p=0.001)] and anodal-transcranial direct current stimulation (a-tDCS) alone (0.655, 95% CI: 0.273 to 1.038, p=0.001) reduced crowding in peripheral vision. The effects of NIBS on visual acuity, motion perception and reaction time were not statistically significant. ConclusionsThere are significant effects of visual cortex NIBS on contrast sensitivity, VEP amplitude, an index of cortical excitability, and crowding among normally sighted individuals. Future studies with robust experimental designs are needed to substantiate these findings in populations with vision loss. PROSPERO registration numberCRD42021255882 HighlightsO_LIWe conducted a meta-analysis and a systematic review on the efficacy of non-invasive brain stimulation for improving on visual function C_LIO_LIVisual cortex non-invasive brain stimulation can enhance contrast sensitivity, reduce crowding in peripheral vision and enhance visually evoked potential amplitude among normally sighted individuals. C_LI

neuroscience↗

bioRxiv2022

Activation of the fear-responsive anterior hypothalamic area promotes avoidance and triggers compulsive grooming behavior in mice

The anterior hypothalamic area (AHA) is a key brain region for orchestrating defensive behaviors. Here, we first examined AHA activity patterns during fear conditioning using in vivo functional imaging. We observed that neuronal activity in the AHA increases during both foot shock delivery and foot-shock associated auditory cues. Moreover, we used a combination of optogenetics and behavioral assays to determine the functional connectivity between the ventromedial hypothalamus (VMH) and the AHA. We found that photoactivation of the VMH[->]AHA pathway is aversive and triggers compulsive grooming behavior. Furthermore, we observed spatial and temporal changes of grooming behavior during the periods following VMH[->]AHA photoactivation. Interestingly, whole brain metabolic mapping using positron emission tomography (PET) combined with optogenetic activation of the VMH[->]AHA pathway in anesthetized mice revealed the amygdala as a downstream area activated by the stimulation of this pathway. Together, our findings show that the AHA responds to threat and that such increases in activity are sufficient to trigger compulsive grooming behavior. Thus, our results may help to understand some neuropsychiatric disorders characterized by repetitive and compulsive behaviors.

neuroscience↗