Biology subjects

Wong, Y.-H.

Publications and source records attributed to Wong, Y.-H..

3 recordsLinked to original sources

bioRxiv2026

Repurposed COMT Inhibitors Tolcapone and Entacapone Selectively Suppress Aggregation and Seeding of P301 Mutant TAU in Human Neuronal Models

Background and PurposePathogenic aggregation and propagation of seed-competent TAU assemblies drive tauopathies. MAPT P301 mutations accelerate aggregation and enhance seed competence, yet pharmacological strategies selectively targeting these pathogenic species remain limited. We investigated whether the clinically approved catechol-O-methyltransferase inhibitors tolcapone (TOL) and entacapone (ENT) preferentially modulate mutant TAU aggregation and seeding. Experimental ApproachTOL and ENT effects on TAU aggregation were evaluated via cell-free assays, surface plasmon resonance (SPR), and in silico docking. Functional consequences of compound-modified fibrils were assessed in mutant TAU-expressing SH-SY5Y cells. Translational relevance was examined in human induced pluripotent stem cell (hiPSC)-derived neurons exposed to pathogenic K18 fibrils, followed by post-seeding compound treatment. Key ResultsBoth compounds dose-dependently inhibited TAU aggregation, exhibiting greater potency, stronger SPR binding affinities, and more favorable computed interaction energies for P301S mutant versus wild-type TAU. Fibrils formed with TOL or ENT induced less downstream TAU oligomerization and phosphorylation in SH-SY5Y cells, with TOL showing superior protection. In hiPSC-derived neurons, post-seeding treatment with either compound decreased fibril-induced, sarkosyl-insoluble TAU aggregation and phosphorylation without overt cytotoxicity. Conclusion and ImplicationsTOL and ENT preferentially inhibit the aggregation and seeding of pathogenic P301 mutant TAU. This supports mutation-focused pharmacological strategies and highlights catechol scaffolds as viable starting points for the development of disease-modifying therapeutics. Future research must determine the precise interaction mechanisms with aggregation intermediates and evaluate in vivo efficacy in animal models.

neuroscience↗

bioRxiv2023

The efficient induction of human retinal ganglion-like cells provides a platform for studying optic neuropathies

Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and cell death; this can result in irreversible vision loss. Here we developed a rapid protocol for directly inducing RGC differentiation from human induced pluripotent stem cells (iPSCs) by the overexpression of ATOH7, BRN3B and SOX4. The hiPSC-derived RGC-like cells (iRGCs) show robust expression of various RGC-specific markers by whole transcriptome profiling. A functional assessment was also carried out and this demonstrated that these iRGCs display stimulus-induced neuronal activity, as well as spontaneous neuronal activity. Ethambutol (EMB), an effective first-line anti-tuberculosis agent, is known to cause serious visual impairment and irreversible vision loss due to the RGC degeneration in a significant number of treated patients. Using our iRGCs, EMB was found to induce significant dose-dependent and time-dependent increases in cell death and neurite degeneration. Western blot analysis revealed that the expression levels of p62 and LC3-II were upregulated, and further investigations revealed that EMB caused a blockade of lysosome-autophagosome fusion; this indicates that impairment of autophagic flux is one of the adverse effects of that EMB has on iRGCs. In addition, EMB was found to elevate intracellular reactive oxygen species (ROS) levels increasing apoptotic cell death. This could be partially rescued by the co-treatment with the ROS scavenger NAC. Taken together, our findings suggest that this iRGC model, which achieves both high yield and high purity, is suitable for investigating optic neuropathies, as well as being useful when searching for potential drugs for therapeutic treatment and/or disease prevention.

cell biology↗

bioRxiv2017

Implications of de novo mutations in guiding drug discovery: A study of four neuropsychiatric disorders

Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored.\n\nIn this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations. Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning.

genomics↗