Biology subjects

Lim, C. M.

Publications and source records attributed to Lim, C. M..

10 recordsLinked to original sources

bioRxiv2026

Microglia as transcriptional pacemakers of neuronal aging heterogeneity across individuals

Neuronal aging pace varies markedly between individuals, but what drives this variation remains unknown. Using cell-type-specific transcriptomic clocks applied to single-nucleus RNA sequencing data from 226 adults (ages 20-90), we quantified neuronal aging residuals as a donor-dominant phenotype. Variance decomposition revealed that microglial transcriptional programs predict inter-individual variation in neuronal aging residuals, a directional asymmetry consistent with a non-cell-autonomous relationship between microglial states and neuronal aging trajectories. This asymmetry is accompanied by an age-dependent shift from homeostatic to inflammatory microglial dominance beginning in midlife, with inflammatory dominance probability rising from 26% at age 35 to 92% by age 65, replicated in an independent cohort. IFN{gamma} signaling emerges as the dominant microglial program associated with accelerated neuronal aging in late adulthood. Candidate regulators of microglial IFN{gamma} activity (HIF1A, CEBPB, and EZH2) are computationally prioritized as intervention targets warranting functional validation.

neuroscience↗

bioRxiv2025

Linking Aβ and tau in the amyloid cascade through the intersection of their proteostasis networks

Amyloid plaques and neurofibrillary tangles are molecular hallmarks of Alzheimers disease. According to the amyloid cascade hypothesis, aberrant A{beta} and tau behaviours contribute synergistically to accelerate the Alzheimers pathology. However, the complex molecular mechanisms linking A{beta} and tau dysregulation remain to be fully characterised. To address this problem, we investigated the connection between A{beta} and tau through the protein homeostasis (proteostasis) network. We asked whether A{beta} proteostasis is linked to tau proteostasis. To answer to this question, we first mapped the proteostasis networks of A{beta} and tau, and then studied the interplay of these two networks, identifying the molecular chaperone HSP90 as a central hub. To test this hub role of HSP90, we observed in a cell model that HSP90 and its co-chaperone SUGT1 mediate tau phosphorylation via GSK-3{beta} in an A{beta}42-dependent manner. Furthermore, we also observed that in turn HSP90 and SUGT1 increase the intracellular concentration of A{beta}42. These results suggest that the HSP90/SUGT1 system may act as a hub in the amyloid cascade by lying at the intersection of the A{beta} and tau proteostasis networks.

neuroscience↗

bioRxiv2025

The alpha-Synuclein Proteostasis Network and its Translational Applications in Parkinson's disease

Parkinsons disease (PD) is debilitating neurodegenerative condition that results in the loss of mobility and muscle control. A neuropathological hallmark of PD is the presence aberrant inclusions, known as Lewy pathology, of which -synuclein (-Syn) is a major component. The accumulation of -Syn is a likely consequence of an age-related impairment of the proteostasis system regulating -Syn. To investigate this phenomenon, we map the proteostasis network (PN) of -Syn in the Substania nigra at the proteomic and transcriptomic levels. We then define a -Syn proteostasis activity score (PAS) that quantifies the activity of the PN in regulating -Syn. We thus obtain a PAS signature indicative of the disease state, as well as the age-of-death in PD patients, and the brain regional vulnerability to -Syn aggregation. We then outline a digital twin of the -Syn PN in the Substantia nigra cells by training a model on single-cell data. This digital twin is applied towards target identification for PD. In addition, we further describe the application of the PN to facilitate drug repurposing. Overall, our study highlights the implication of the -Syn PN in PD and how simulations and measurements of its activity can help efforts in translational research for PD.

neuroscience↗

bioRxiv2024

Proteostasis Signatures in Human Diseases

The protein homeostasis (proteostasis) system maintains the proteome in a healthy state. Although this system has been comprehensively mapped, its perturbations in disease remain incompletely characterised. To address this problem, here we define the proteostasis signatures, which represent the characteristic patterns of change in the proteostasis system associated with disease. We performed a large-scale, pandisease analysis across 32 human diseases spanning 7 disease types. We first identified unique proteostasis perturbations in specific disease states. We then uncovered distinctive signatures differentiating disease types, pointing to a range of proteostasis mechanisms in disease development. Next, we tracked the temporal evolution of proteostasis signatures, revealing shifts in proteostasis disruption over the course of disease progression. Finally, we demonstrated how smoking, a major risk factor of many diseases, impairs proteostasis in a manner similar to disease, potentially creating a predisposed environment for disease onset. These results illustrate the opportunities offered by the study of human diseases from the perspective of proteostasis signatures.

bioinformatics↗

bioRxiv2024

Immuno-moodulin is Differentially Expressed in T Cells and Plasma in Obsessive-Compulsive Disorder Patients

Immuno-moodulin (Imood), a recently discovered protein expressed in T cells, is associated with anxiety-like behavior in mice. However, its mechanism of action in modulating neuroimmune interactions remains unclear. To investigate this problem, we characterized Imood in human blood and immune cells using neutralizing monoclonal antibodies, revealing its nature as an intrinsically disordered protein (IDP) with unique expression patterns. Our findings indicate that Imood is predominantly expressed intracellularly in peripheral blood mononuclear cells (PBMCs), particularly T lymphocytes, but is absent in polymorphonuclear cells. Upon T-cell activation, Imood exhibits distinct mobilization patterns with increased surface expression. Bioinformatics analysis identified a strong propensity for oligomerization and liquid-liquid phase separation. We also found that T cells from patients with Obsessive-Compulsive-Disorder (OCD) displayed significantly elevated surface Imood expression compared to healthy controls, as well as an altered level of Imood polymerization in the plasma. Taken together, these results elucidate the expression patterns and structural properties of Imood in human immune cells, which open new avenues for OCD diagnostics, and prompt further study for understanding the aetiology of OCD and related disorders.

immunology↗

bioRxiv2024

Organization of the Proteostasis Network of Membraneless Organelles

Membraneless organelles (MLOs) are dynamic macromolecular condensates that act as crucibles to modulate biological process within the cell. Since MLOs form in the absence of lipid membranes, it is important to understand how their effective regulation is achieved by the protein homeostasis (proteostasis) system. To address this question, we report a comprehensive mapping of the proteostasis network (PN) of MLOs, comprising over 220,000 protein-protein interactions. The analysis of this PN reveals how the regulatory proteins (PN proteins) occupy central roles in the overall protein-protein interaction network of MLOs. We then investigate which branches of the PN are most important in the regulation of MLOs, and find that the anabolic component, which makes up [~]30% of the PN, is more closely involved with MLOs than the catabolic component, which makes up the remaining [~]70% of the PN. We also find that translation-related PN proteins and molecular chaperones play central roles in the regulation of MLOs. We then analyse the similarity between the PNs of different MLOs, revealing that stress granules and P-bodies share large portions of their PNs. Finally, to understand how specificity is achieved despite these similarities, we further analyse the PN organization, showing that HSP70 chaperones are generic in regulating MLOs, while client-specific HSP70 co-chaperones confer specificity to the chaperone action. Taken together, these results identify the composition of the PN of MLOs, rationalize its organization, and reveal a central role of molecular chaperones in the regulation of protein conformations within MLOs.

bioinformatics↗

bioRxiv2024

A human neuronal model of sporadic Alzheimer's disease induced by FBXO2 downregulation shows A β aggregation, tau hyperphosphorylation and functional network impairment

Sporadic Alzheimers disease (sAD) arises from a complex interplay between genetic and environmental factors that remains poorly understood, making it challenging to develop accurate cell models. To address this problem, by hypothesing that the early disease sAD states can be characterised by transcriptomic fingerprints, we assessed the effect on A{beta} aggregation in human neuroblastoma cells a set of genes obtained by analysing snRNA-seq data from post-mortem AD patients. We then validated the most effective genes in human iPSC-derived cortical neurons, and selected FBXO2, a gene encoding a subunit of the ubiquitin protein ligase complex SCF, for further analysis. We found that early downregulation of FBXO2 in human iPSC-derived cortical neurons resulted in A{beta} aggregation, tau hyperphosphorylation, and structural and functional neuronal network impairment. Based on these results, we report a neuronal sAD model (FBXO2 KD sAD) that recapitulates a set of molecular hallmarks of sAD. We suggest that this strategy can be expanded towards the generation of panels of preclinical stem cell-derived models that recapitulate the molecular complexity of the broad spectrum of AD patients.

neuroscience↗

bioRxiv2024

Antiviral effect of betacyanins from red pitahaya (Hylocereus polyrhizus) against influenza A virus

Seasonal influenza affects millions of lives worldwide, with influenza A virus (IAV) responsible for pandemics and annual epidemics, causing the most severe illnesses resulting in patient hospitalizations or death. With IAV threatening the next global influenza pandemic, it is a race against time to search for antiviral drugs. Betacyanins are unique nitrogen-containing and water-soluble reddish-violet pigments that have been reported to possess antiviral properties against dengue virus. The objective of this study was to examine the antiviral effect of betacyanins from red pitahaya (Hylocereus polyrhizus) on IAV-infected lung epithelial A549 cells. HPLC and LC-MS analysis of extracted betacyanin showed four betacyanins in the betacyanin fraction, namely phyllocactin, hylocerenin, betanin, and isobetanin. Cytotoxicity assay showed that betacyanin fractions were not cytotoxic to A549 cells at concentrations below 100 {micro}g/mL. Betacyanin fraction concentrations of 12.5, 25.0, and 50.0 {micro}g/mL prevented the formation of viral cytopathic effect and reduced virus titer in IAV-infected cells up to 72 h. A downregulation of protein and mRNA nucleoprotein expression levels was observed after treatment with 25.0 and 50.0 {micro}g/mL of betacyanin fraction after 24 h, thereby providing evidence for the anti-viral activity of betacyanin from red pitahaya against IAV in vitro.

microbiology↗

bioRxiv2023

In silico Antibody-Peptide Epitope prediction for Personalized cancer therapy

The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encodes cell-surface proteins responsible for regulating the immune system. Viral peptides presented to cancer cell surfaces by the HLA trigger the immune system to kill the cells, creating Antibody-peptide epitopes (APE). This study proposes an in-silico approach to identify patient-specific APEs by applying complex networks diagnostics on a novel multiplex data structure as input for a deep learning model. The proposed analytical model identifies patient and tumor-specific APEs with as few as 20 labeled data points. Additionally, the proposed data structure employs complex network theory and other statistical approaches that can better explain and reduce the black box effect of deep learning. The proposed approach achieves an F1-score of 80% and 93% on patients one and two respectively and above 90% on tumor-specific tasks. Additionally, it minimizes the required training time and the number of parameters.

cancer biology↗

bioRxiv2021

Copper signaling promotes proteostasis and animal development via allosteric activation of ubiquitin E2D conjugases

Nutrient copper supply is critical for cell growth and differentiation, and its disturbance is associated with major pathologies including cancer and neurodegeneration. Although increasing copper bioavailability in late Precambrian facilitated emergence of novel cuproproteins, their intricate regulation by this essential trace element remains largely cryptic. We found that subtle rises in cellular copper strikingly increase polyubiquitination and accelerate protein degradation within 30 minutes in numerous mammalian cell lines. We track this surprising observation to allostery induced in the UBE2D ubiquitin conjugase clade through a conserved CXXXC sub-femtomolar-affinity Cu+ binding motif. Thus, physiologic fluctuation in cytoplasmic Cu+ is coupled to the prompt degradation of UBE2D protein targets, including p53. In Drosophila harboring a larval-lethal knockdown of the nearly identical fly orthologue UbcD1, complementation with human UBE2D2 restored near-normal development, but mutation of its CXXXC Cu+ binding motif profoundly disrupted organogenesis. Nutrient Cu+ emerges as a trophic allosteric modulator of UBE2D activity through a structural motif whose evolution coincides with animal multicellularity. One Sentence SummaryModulation of nutrient copper impacts protein turnover and animal morphogenesis through conserved allostery of ubiquitin E2D conjugases. HilightsO_LINutrient copper supply is critical for cell growth and differentiation C_LIO_LIThe E2D clade of ubiquitin conjugases contains a sub-femtomolar-affinity Cu+ binding motif C_LIO_LIAllosteric activation by Cu+ markedly accelerates protein polyubiquitination C_LIO_LIThis sensor couples physiologic fluctuations in cytoplasmic Cu+ with the degradation rate of E2D targets, including p53 C_LIO_LIThis metazoan signaling mechanism is critical for drosophila morphogenesis C_LI In BriefConserved allostery of ubiquitin E2D conjugases links nutrient copper signaling to protein degradation and animal morphogenesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/431211v2_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@17009fforg.highwire.dtl.DTLVardef@a07f8eorg.highwire.dtl.DTLVardef@11664c7org.highwire.dtl.DTLVardef@1327ab7_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

biochemistry↗