Biology subjects

Huang, Y.-W. A.

Publications and source records attributed to Huang, Y.-W. A..

7 recordsLinked to original sources

bioRxiv2026

Neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis that promotes synapse remodeling

Neuron-microglia communication shapes neuroimmune homeostasis and circuit maturation, yet the neuron-derived cues that tune microglial inflammatory state and phagocytic programs remain incompletely defined. The E3 ubiquitin ligase UBE3A is critical for brain development and synaptic function, and altered UBE3A dosage or activity is linked to neurodevelopmental phenotypes with emerging connections to inflammation. Using Angelman syndrome (AS), where UBE3A loss is largely neuron-selective due to imprinting, as a tractable framework, we investigated how neuronal UBE3A deficiency engages microglial programs. In human iPSC-derived neuron-microglia co-cultures, neuronal UBE3A depletion induced a TNF-associated secretory signature and was accompanied by increased microglial inflammatory markers, including complement components. Neuron-conditioned media was sufficient to elicit microglial cytokine/complement transcripts, supporting a role for soluble neuron-derived cues. In these co-cultures, neuronal UBE3A loss increased synapse engulfment by microglia, which was reduced by TNF receptor pathway inhibition with the TNFR1 antagonist R7050 alongside decreased microglial inflammatory readouts. In vivo, juvenile AS mouse hippocampus showed early microglial dysregulation, and reanalysis of a maternal-deletion AS pig single-nucleus RNA-seq dataset revealed enrichment of microglial activation and phagosome/lysosome pathways. Together, these findings implicate a TNF-linked neuron-to-microglia signaling axis downstream of neuronal UBE3A loss that can be pharmacologically modulated during development.

neuroscience↗

bioRxiv2026

Targeting UBE3A and downstream estrogen receptor-β signaling to restore oligodendroglial homeostasis in Angelman syndrome

Mutations that reduce UBE3A cause Angelman syndrome (AS), a neurodevelopmental disorder marked by severe developmental delay and neuropsychiatric symptoms. Although UBE3A has been studied primarily in neurons, it is also expressed in the oligodendrocyte lineage, raising the possibility that glial dysfunction contributes to disease phenotypes. Here we identify an intrinsic, UBE3A-dependent mechanism that governs oligodendrocyte precursor cell (OPC) homeostasis, a process necessary for normal myelination. Using human iPSC-derived OPCs, we performed a targeted compound screen and found that loss of UBE3A diminishes estrogen receptor-{beta} (ESR{beta}) signaling, leading to impaired OPC self-renewal. Mechanistically, UBE3A sustains ESR{beta} levels in OPCs and thereby maintains downstream signaling required for OPC proliferation and stable OPC density. To address cell-type specificity and neuron-glia interactions, we combined oligodendrocyte-lineage-restricted Ube3a knockdown in vivo with reductionist iPSC neuron-OPC co-culture assays, which together support an intrinsic requirement for oligodendroglial UBE3A in OPC proliferation and myelination. Pharmacologic activation of ESR{beta} with selective agonists restored OPC self-renewal and myelination deficits in AS patient iPSC-based systems and rescued oligodendroglial and behavioral abnormalities in AS mouse models. Notably, ESR{beta} signaling primarily regulates OPC homeostasis rather than directly driving oligodendrocyte differentiation, pinpointing a stage-specific therapeutic entry point. These findings highlight a tractable oligodendroglial pathway downstream of UBE3A with translational potential for AS. One Sentence SummaryUBE3A regulates oligodendroglial homeostasis for myelination via estrogen receptor-{beta} signaling as a therapeutic target for Angelman syndrome.

neuroscience↗

bioRxiv2026

Stage-specific CHI3L1/YKL-40 signaling controls generation of oligodendrocyte precursor cells through IL13Rα2-mediated ferroptosis

Oligodendrocyte precursor cells (OPCs) are essential for sustaining myelin plasticity and maintaining oligodendroglial homeostasis throughout life. However, the intrinsic signaling mechanisms that regulate OPC generation from neural progenitors remain incompletely understood. Here, we identify chitinase-3-like protein 1 (CHI3L1/YKL-40) as a stage-specific, intrinsic signaling regulator of oligodendroglial lineage progression. Using human iPSC-derived models, we show that CHI3L1 selectively targets a transient IL13R2-expressing pre-OPC population, where it induces ferroptosis through suppression of GPX4, thereby limiting OPC generation. In contrast, CHI3L1 does not trigger cell death in established OPCs but instead suppresses their proliferation and differentiation while promoting a reactive, immune-like transcriptional state. Mechanistically, IL13R2 mediates CHI3L1-dependent ferroptotic vulnerability at the pre-OPC stage, distinguishing it from parallel signaling pathways that regulate neuronal differentiation. Functionally, this dual-stage regulation constrains the production and maintenance of OPCs, a critical determinant of oligodendroglial homeostasis and myelin plasticity. These findings define an intrinsic signaling axis that couples stage-specific cell fate vulnerability to ferroptotic cell death, thereby controlling OPC pool dynamics with broad implications for cognitive function and disorders involving disrupted myelination.

neuroscience↗

bioRxiv2024

Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor TrkB, have a well-established role as regulators of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Previously, we reported that the association of PSD-95 with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLC{gamma} and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of NDDs. To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

neuroscience↗

bioRxiv2022

Nanometer-Resolution Long-term Tracking of Single Cargos Reveals Dynein Motor Mechanisms

Cytoplasmic dynein is essential for intracellular transport, but because of its complexity, we still do not fully understand how this 1.5 megadalton protein works. Here, we used novel optical probes that enable single-particle tracking (SPT) of individual cargos transported by dynein motors in live neurons over 900 m. Analyses using the Fluctuation Theorem (FT) showed that the number of dynein molecules switches between 1-5 motors during the transport. Clearly resolved single-molecular steps revealed that the dwell times between individual steps were accurately described by an enzymatic cycle dominated by two equal and thermally-activated rate constants. Based on these data, we propose a new molecular model whereby each step requires the hydrolysis of 2 ATPs. The model is consistent with extensive structural, single-molecule and biochemical measurements.

biophysics↗

bioRxiv2020

Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-Derived NRXN1-Mutant Neurons

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation predisposing to schizophrenia. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

neuroscience↗

bioRxiv2018

ApoE2, ApoE3 and ApoE4 Differentially Impact Multiple Signaling Pathways Regulating Synaptogenesis

Apolipoprotein E (ApoE) mediates clearance of circulating lipoproteins from blood by binding to ApoE receptors. Humans express three genetic variants, ApoE2, ApoE3, and ApoE4, that exhibit distinct ApoE receptor binding properties. In brain, ApoE is abundantly produced by activated astrocytes and microglia, and three variants differentially affect Alzheimers disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to the disease. A role for ApoE4 in driving microglial dysregulation and impeding A{beta} clearance in AD is well documented, but the direct effects of three variants on neurons are poorly understood. Extending previous studies, we here demonstrate that ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades which among others enhance synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted paracrine signal and activates neuronal signaling pathways in what may represent a protective response, with the differential potency of ApoE variants causing distinct levels of chronic signaling that may contribute to AD pathogenesis.

molecular biology↗