Biology subjects

Zhang, Y.-C.

Publications and source records attributed to Zhang, Y.-C..

4 recordsLinked to original sources

bioRxiv2026

Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Transforming growth factor {beta}-activated kinase 1 (TAK1) is a serine/threonine kinase best known for its roles in immune and stress-response signaling, yet its physiological function in mature neurons remains poorly understood. Here we identify neuronal TAK1 as a regulator of excitatory synaptic integrity, hippocampal plasticity and memory. Conditional reduction of TAK1 in forebrain excitatory neurons impaired short- and long-term memory and was accompanied by attenuated long-term potentiation in the hippocampus. At the cellular level, TAK1 deficiency reduced dendritic spine density and suppressed excitatory synaptic transmission, whereas genetic or pharmacological disruption of TAK1 kinase activity recapitulated these synaptic deficits. Mechanistically, TAK1 localized to the postsynaptic compartment of excitatory synapses and associated with PSD-95. Phosphoproteomic analysis of isolated postsynaptic density fractions revealed coordinated changes in synaptic phosphorylation following TAK1 reduction, including decreased phosphorylation of the NMDA receptor subunit GluN2B at serine 920. Analyses of phosphodeficient and phosphomimetic GluN2B mutants supported a role for S920 phosphorylation downstream of TAK1 in maintaining dendritic spine density, excitatory synaptic transmission and spontaneous synaptic calcium activity. Notably, synaptic TAK1 level was reduced in the aged hippocampus. Re-expressing neuronal TAK1 in aged mice increased dendritic spine density, enhanced hippocampal synaptic plasticity, and improved memory performance. Together, these findings define a postsynaptic TAK1-GluN2B signaling axis that supports excitatory synaptic function and suggest that reduced synaptic TAK1 signaling may contribute to hippocampal vulnerability during aging.

neuroscience↗

bioRxiv2025

α2A-AR-Kv dysfunction drives LC hyperactivity and early sleep disturbance in amyloidogenic mice

Disrupted sleep-wake patterns are common in neurodegenerative disorders such as Alzheimers disease (AD), can emerge early, and are proposed as potent risk factors for disease onset and progression. However, the underlying mechanisms remain poorly understood. Here, we report that 5xFAD transgenic mice exhibit hyperarousal and reduced brain-state transitions, particularly during the dark phase, as early as two months of age. The Locus Coeruleus (LC), a key regulator of arousal and brain-state transitions and a region highly vulnerable in AD, shows time-specific hyperactivity during this phase. This increased tonic LC activity is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 potassium channel conductance. Pharmacological activation of 2A adrenergic receptors restored Kv4 and Kv7 function and normalized LC activity. Furthermore, local administration of the 2A agonist guanfacine or the Kv7 positive allosteric modulator retigabine substantially rescued the sleep-wake disturbances in young 5xFAD mice. These findings identify dark-phase-selective LC hyperexcitability as a key driver of early-onset sleep disruption in AD mice and implicate 2A adrenergic receptors and Kv7 channels as promising targets for early intervention.

neuroscience↗

bioRxiv2023

Lactylation-driven FTO-mediated m6A modification of CDK2 aggravates diabetic microvascular anomalies

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. FTO is an N6-methyladenosine (m6A) demethylase that participates in various biological events, while its role in DR remains elusive. Herein, we detected elevated FTO expression in retinal proliferative membranes of DR patients. FTO promoted endothelial cell (EC) cell cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC-microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate mediated histone lactylation. FB23-2, an inhibitor to FTOs m6A demethylase activity, suppressed angiogenic phenotypes in vivo and in vitro. Noteworthy, we developed a nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficiencies in mice. Collectively, our study demonstrated that FTO coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR.

cell biology↗

bioRxiv2019

EuRBPDB: a comprehensive resource for annotation, functional and oncological investigation of eukaryotic RNA binding proteins (RBPs)

RNA binding proteins (RBPs) are a large protein family that plays important roles at almost all levels of gene regulation through interacting with RNAs, and contributes to numerous biological processes. However, the complete list of eukaryotic RBPs including human is still unavailable. In this study, we systematically identified RBPs in 162 eukaryotic species based on both computational analysis of RNA binding domains (RBDs) and large-scale RNA binding proteomic (RBPome) data, and established a comprehensive eukaryotic RBP database, EuRBPDB (http://EuRBPDB.syshospital.org:8081). We identified a total of 311,571 RBPs with RBDs and 3,639 non-canonical RBPs without known RBDs. EuRBPDB provides detailed annotations for each RBP, including basic information and functional annotation. Moreover, we systematically investigated RBPs in the context of cancer biology based on published literatures and large-scale omics data. To facilitate the exploration of the clinical relevance of RBPs, we additionally designed a cancer web interface to systematically and interactively display the biological features of RBPs in various types of cancers. EuRBPDB has a user-friendly web interface with browse and search functions, as well as data downloading function. We expect that EuRBPDB will be a widely-used resource and platform for the RNA biology community.

bioinformatics↗