Biology subjects

Ch'ng, T. H.

Publications and source records attributed to Ch'ng, T. H..

3 recordsLinked to original sources

bioRxiv2025

Anti-isoDGR Antibody Inhibits Atherosclerosis Induced by Western Diet in ApoE-/- mice

BackgroundDegenerative protein modifications (DPMs) accumulate with aging and can alter biomolecule structure and function, including via spontaneous conversion of Asn-Gly-Arg (NGR) to isoAsp-Gly-Arg (isoDGR) motifs that can bind integrins and drive chronic inflammation. Since isoDGR-modified extracellular matrix proteins are enriched in atherosclerosis and have been associated with rupture-prone plaque characteristics, we hypothesized that antibody neutralisation can inhibit key pathological features including atherosclerotic vascular plaque formation and metabolic dysfunction. MethodsWe first examined Pcmt1-/- mice which rapidly accumulate isoDGR due to lack of the corresponding repair enzyme to assess the extent of vascular protein damage. We then treated 6-8 week old atherosclerosis-prone (ApoE-/-) mice which were fed a high-fat Western diet (WD) with weekly dose of 1mg/kg isoDGR-specific monoclonal antibody (isoDGR-mAb) or isotype-matched control (while on diet) for 2 months duration. A regular chow-fed ApoE-/- group served as baseline control. Aortic atherosclerotic burden, plaque composition, systemic inflammation, lipid profiles, hepatic steatosis, and metabolic parameters (indirect calorimetry) were assessed. ResultsPcmt1-/- mice displayed extensive isoDGR deposition and degeneration of the aortic wall, linking this DPM to vascular structural damage. In the ApoE-/- mice, WD induced large aortic root plaques with abundant isoDGR and macrophage infiltration. IsoDGR-mAb treatment decreased plaque size by [~]30% with reduced lipid and collagen content (p=0.001). Furthermore, plaques in treated mice contained significantly fewer CD68+ macrophages that also exhibited limited activation. Systemically, isoDGR-mAb modified lipoprotein profiles by decreasing atherogenic VLDL/IDL/LDL cholesterol (p=0.04) while slightly increasing HDL, accompanied by a reduction in circulating inflammatory proteins. IsoDGR-mAb also protected against hepatic lipid accumulation which was reduced by [~]60% in treated animals (p<0.001), with indirect calorimetry confirming [~]30% higher oxygen consumption and energy expenditure without change in food intake or physical activity. ConclusionWe identified isoDGR as a key pathological factor involved in the progression of atherosclerosis. Remarkably, isoDGR neutralization diminished plaque inflammation and improved atherosclerotic plaque stability. Our findings support isoDGR neutralization as a promising therapeutic strategy to mitigate both atherosclerosis and aging-associated metabolic dysfunction.

pharmacology and toxicology↗

bioRxiv2024

Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease

The emergence of A{beta} pathology is one of the hallmarks of Alzheimers disease (AD), but the mechanisms and impact of A{beta} in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope and its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of A{beta} on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses A{beta} in young animals. Our studies revealed that a time-dependent accumulation of intracellular A{beta} corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction App KI neurons become more vulnerable to inflammation-induced necroptosis - a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates A{beta} in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.

neuroscience↗

bioRxiv2020

LOCAL REGULATION AND FUNCTION OF IMPORTIN-β1 DURING TRANSCRIPTION-DEPENDENT PLASTICITY

Activity-dependent transcription is critical for the encoding of long-term memories. Regulated nuclear entry of soluble proteins is one method to relay synaptic signals to the nucleus to couple neuronal excitation with transcription. To date, the role of importin-{beta}1 in nuclear shuttling of proteins during activity-dependent transcription has always been inferred but not directly investigated. In this study, we demonstrate activity-dependent nuclear accumulation of importin-{beta}1 from the soma and the synapto-dendritic compartments. Importantly, inhibition of importin-{beta}1 mediated nuclear import during synaptic stimulation impairs long-term plasticity. We show evidence that importin-{beta}1 mRNA-ribosome complex is distributed throughout the synapto-dendritic compartment and synaptic stimulation induces importin-{beta}1 local protein synthesis. Finally, we identified candidate proteins that associate with importin-{beta}1 at the synapse and characterize NDRG1 as an importin-{beta}1 interactor that undergoes activity-dependent translocation into the nucleus. Collectively, our results highlight the crucial role of importin-{beta}1 in the nuclear import of soluble proteins during long-term plasticity.

neuroscience↗