Biology subjects

Wong, M. Y.

Publications and source records attributed to Wong, M. Y..

At least 19 recordsLinked to original sources

bioRxiv2026

TRAPPC8 Is an Endogenous Brake on UFMylation That Suppresses Tauopathy

UFMylation, a ubiquitin-like protein modification, drives tau spread through the brain, but what keeps this process in check has remained unclear. We show that TRAPPC8 acts as a natural brake on UFMylation, binding directly to the E1 enzyme UBA5 to dampen pathway activity. In Alzheimer's disease brain tissue, TRAPPC8 is reduced while UFMylation is elevated, suggesting this brake fails as disease progresses. Sustaining UFMylation in human iPSC-derived neurons increased tau aggregation and spread while disrupting lysosomal function and lipid balance. Restoring TRAPPC8-UBA5 binding reversed these defects through the lysosomal protein CLN8, which restored lysosomal function and reduced tau pathology. Notably, expressing just the UBA5-binding region of TRAPPC8 was enough to suppress tau pathology in vivo, marking it as a promising therapeutic target.

neuroscience↗

bioRxiv2026

Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.

neuroscience↗

bioRxiv2026

Microglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity

Microglia continuously survey the brain and shape neuronal activity, but their contribution to experience-dependent synaptic plasticity is unclear. Levodopa-induced dyskinesia (LID) is a disabling complication of late-stage Parkinsons disease (PD) that is linked to maladaptive striatal remodeling and is often assumed to reflect detrimental neuroinflammation. Here we identify a dyskinesia-associated microglial gene program in the striatum of PD patients and show that microglia instead act as a protective brake on LID. In a mouse model, microglial depletion exacerbated dyskinesia, whereas microglial repopulation mitigated it. Delivery of AAV expressing soluble TREM2 (sTREM2) similarly reduced LID without impairing the therapeutic benefit of levodopa. Single-nucleus transcriptomics revealed that microglial loss drives extensive remodeling of both direct and indirect spiny projection neurons (SPNs), while repopulation or sTREM2 reverses a large fraction of LID-associated transcriptional changes. Mechanistically, sTREM2 directly engages TrkB and potentiates BDNF-dependent TrkB-ERK signaling, consistent with positive allosteric modulation. Functionally, sTREM2 enhances BDNF-TrkB-dependent hippocampal synaptic plasticity and acutely rebalances striatal dendritic excitability in a compartment- and cell type-specific manner. These findings reveal an unexpected neuroimmune pathway in which microglia restrain maladaptive plasticity via sTREM2-TrkB signaling, with therapeutic implications.

neuroscience↗

bioRxiv2026

cGAS inhibition delays TDP-43-driven ALS Pathogenesis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.

neuroscience↗

bioRxiv2026

cGAS-mediated IFN-I signaling contributes to disease progression in drug-refractory epilepsy

Epilepsy is a prevalent neurological disease with a third of patients becoming non-responsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we report that DRE disease progression is contributed by overactive cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN-I) signaling. In human DRE microglia, we observe a robust IFN-I signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we observe the activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS reduces epileptic phenotypes, glial inflammatory signatures, and neuronal transcriptomic changes, underscoring the therapeutic potential of targeting cGAS for DRE treatment.

neuroscience↗

bioRxiv2026

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglia (iMG) into progranulin (Grn)-deficient mice. We find that wild-type, but not Grn-deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders. One Sentence SummaryOur study demonstrates that xenotransplantation of wild-type human iPSC-derived microglia into progranulin-deficient mice mitigates core neuropathological, network-level, and behavioral features of Frontotemporal Dementia.

neuroscience↗

bioRxiv2025

STING_IFN_CH25H lipid axis links innate immune activation to tau pathology

Genetic risk for Alzheimers disease is strongly enriched in pathways governing microglial activation and cholesterol metabolism, yet how these processes converge to drive neurodegeneration remains unclear. Here, we identify the oxysterol 25-hydroxycholesterol (25- HC) as a pathogenic lipid downstream of the cGAS-STING-IFN pathway. In models of tau pathology, interferon signaling induces Cholesterol 25-hydroxylase (CH25H) expression in microglia. Ch25h deletion in female P301S mice suppressed tau aggregation, preserved synapses, prevented brain atrophy, and rescued memory. Mechanistically, loss of CH25H disrupted STING trafficking, attenuated IFN activation, dampened self-perpetuating microglial inflammation. Strikingly, 25-HC directly accelerated tau propagation in human iPSC derived neurons. It also disrupted lysosomal and mitochondrial lipid composition, driving cholesteryl ester accumulation and promoting apoptosis under tau-induced stress. These findings define a STING-IFN-CH25H lipid axis that bridges innate immune activation to tau pathology and toxicity, offering a tractable therapeutic pathway for inflammation-driven neurodegenerative conditions.

neuroscience↗

bioRxiv2024

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects of R136S against tauopathy. One-sentence summaryThe R136S mutation on APOE3 enhances resistance to tau-related pathology and toxicity by downregulating the cGAS-STING-IFN signaling pathway.

neuroscience↗

bioRxiv2024

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

The strongest risk factors for Alzheimers disease (AD) include the {chi}4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

neuroscience↗

bioRxiv2023

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Pathogenic tau accumulation fuels neurodegeneration in Alzheimers disease (AD). Enhancing aging brains resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

neuroscience↗

bioRxiv2023

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging

Demyelination occurs in aging and associated diseases, including Alzheimers disease. Several of these diseases exhibit sex differences in prevalence and severity. Biological sex primarily stems from sex chromosomes and gonads releasing sex hormones. To dissect mechanisms underlying sex differences in demyelination of aging brains, we constructed a transcriptomic atlas of cell type-specific responses to illustrate how sex chromosomes, gonads, and their interaction shape responses to demyelination. We found that sex-biased oligodendrocyte and microglial responses are driven by interaction of sex chromosomes and gonads prior to myelin loss. Post demyelination, sex chromosomes mainly guide microglial responses, while gonadal composition influences oligodendrocyte signaling. Significantly, ablation of the X-linked gene Toll-like receptor 7 (Tlr7), which exhibited sex-biased expression during demyelination, abolished the sex-biased responses and protected against demyelination. One-sentence summaryCell type-specific processes underlying aged demyelination are sex-biased and mediated by Tlr7.

neuroscience↗

bioRxiv2023

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.

neuroscience↗

bioRxiv2021

The systematic assessment of completeness of public metadata accompanying omics studies

Recent advances in high-throughput sequencing technologies have made it possible to collect and share a massive amount of omics data, along with its associated metadata. Enhancing metadata availability is critical to ensure data reusability and reproducibility and to facilitate novel biomedical discoveries through effective data reuse. Yet, incomplete metadata accompanying public omics data may hinder reproducibility and reusability by reducing sample interpretability and limiting secondary analyses. In this study, we performed a comprehensive assessment of metadata completeness shared in both scientific publications and/or public repositories by analyzing over 253 studies encompassing over 164 thousands samples, including both human and non-human mammalian studies. We observed that studies often omit over a quarter of important phenotypes, with an average of only 74.8% of them shared either in the text of publication or the corresponding repository. Notably, public repositories alone contained 62% of the metadata, surpassing the textual content of publications by 3.5%. Only 11.5% of studies completely shared all phenotypes, while 37.9% shared less than 40% of the phenotypes. Studies involving non-human samples were more likely to share metadata than studies involving human samples. We observed similar results on the extended dataset spanning 2.1 million samples across over 61,000 studies from the Gene Expression Omnibus repository. The limited availability of metadata reported in our study emphasizes the necessity for improved metadata sharing practices and standardized reporting. Finally, we discuss the numerous benefits of improving the availability and quality of metadata to the scientific community and beyond, supporting data-driven decision-making and policy development in the field of biomedical research. This work provides a scalable framework for evaluating metadata availability and may help guide future policy and infrastructure development.

bioinformatics↗

bioRxiv2021

A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimers disease (AD). PGRN is highly expressed in the microglia near A{beta} plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and A{beta} levels in the young male but not female mice. PGRN deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, Galectin-3, TREM2 and GPNMB, specifically near A{beta} plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to A{beta} fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on amyloid metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia, which may contribute to the disease mechanism associated with PGRN polymorphisms in AD.

neuroscience↗

bioRxiv2021

Cooperative and aggressive behaviours vary between ranks in anemonefish social hierarchies

Many animal groups consist of individuals organised in dominance hierarchies, based on age, size or fighting ability. Lower ranked individuals often do not reproduce themselves but perform cooperative behaviours to help the reproductive output of dominant individuals or the group as a whole. Theoretical models suggest that individuals of higher rank should show increased amounts of aggressive behaviours, such as aggressions towards other group members, but should decrease the amount of cooperative behaviours, such as brood care or territory maintenance. Most empirical tests of these models focus on insect or mammalian systems where kin selection plays a large role, rather than animals that live in groups of unrelated individuals. Here we use two anemonefish species to test hypotheses of variation in cooperation and aggression with respect to social rank and species, for social systems where group members are unrelated. We assessed the behaviours of each rank in 20 groups of Amphiprion percula and 12 groups of A. perideraion in Kimbe Bay, Papua New Guinea. We also performed a removal experiment to test if cooperative and aggressive behaviours are likely adaptive, i.e., if they change as an individual ascends in rank. Our results show differences between the two species, with A. percula showing more cooperative behaviours and A. perideraion showing more aggressive behaviours, despite them being closely related and sharing a very similar ecology. With respect to both cooperation and aggression we found consistent differences between ranks in both species, with higher ranks performing more aggressive as well as more cooperative behaviours. When we experimentally provided lower ranked individuals (rank 4) an opportunity to ascend in the hierarchy, they showed more aggression and more cooperation in line with our observations for rank 3 individuals. Thus, we show that rank specific behavioural patterns are likely adaptive in anemonefishes and that some model predictions do not hold in systems where kin selection benefits are absent. Rather, future fitness benefits through territory inheritance and group augmentation likely motivate cooperative and aggressive behaviours by subordinates in groups of unrelated vertebrates.

animal behavior and cognition↗

bioRxiv2020

Phosphorylation triggers presynaptic phase separation of Liprin-α3 to control active zone structure

Liquid-liquid phase separation enables the assembly of membrane-less subcellular compartments, but testing its biological functions has been difficult. The presynaptic active zone, protein machinery in nerve terminals that defines sites for neurotransmitter release, may be organized through phase separation. Here, we discover that the active zone protein Liprin-3 rapidly and reversibly undergoes phase separation upon phosphorylation by PKC at a single site. RIM and Munc13 are co-recruited to membrane-attached condensates, and phospho-specific antibodies establish Liprin-3 phosphorylation in vivo. At synapses of newly generated Liprin-2/3 double knockout mice, RIM, Munc13 and the pool of releasable vesicles were reduced. Re-expression of Liprin-3 restored these defects, but mutating the Liprin-3 phosphorylation site to abolish phase condensation prevented rescue. Finally, PKC activation acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-3. We conclude that Liprin-3 phosphorylation rapidly triggers presynaptic phase separation to modulate active zone structure and function.

neuroscience↗

bioRxiv2020

Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

Alternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain (www.isoformAtlas.com). Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function.

neuroscience↗

bioRxiv2020

AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

neuroscience↗