Research Lab

Molecular neuroscience: mechanistic study of disease pathogenesis

My group takes a multidisciplinary approach to delineate pathogenic pathways of polyglutamine (polyQ) diseases and other repeat expansion disorders, a group of rare genetic diseases. We reported the role of nucleolar stress in repeat expansion diseases (Tsoi et al., PNAS USA, 2012 Aug 14;109(33):13428-13433). We also study how transcriptional dysregulation contributes to repeat expansion neurodegeneration (Chen et al. Cell Reports, 2018 Sep;19(9):e45409; Peng et al., PNAS USA, 2021 May 11;118(19):e2022940118; Chen et al., Nature Communications, 2023 Dec 18;14(1):8420; Chen et al. doi.org/10.21203/rs.3.rs-2983878/v1). Mechanisms we studied include nucleolar dysfunctioning, small interfering RNA-mediated gene silencing, perturbation of transcriptional regulatory protein networks. More recently, we adopt a spatial transcriptomic approach to further dissect out pathogenic changes in repeat expansion neurodegeneration.

Translational neuroscience: therapeutic development

My group takes a multidisciplinary approach to delineate pathogenic pathways of polyglutamine (polyQ) diseases and other repeat expansion disorders, a group of rare genetic diseases. We reported the role of nucleolar stress in repeat expansion diseases (Tsoi et al., PNAS USA, 2012 Aug 14;109(33):13428-13433). This finding gave us an insight into developing small molecule (Hong et al., Journal of Biological Chemistry, 2019 Feb 22; 294(8):2757-2770; Peng et al., PNAS USA, 2021 May 11;118(19):e2022940118; Chen et al., doi.org/10.21203/rs.3.rs-2983878/v1) and peptidylic (Peng et al., Molecular Therapy Nucleic Acids, 2022 Jun 13;29:102-115; Peng et al., PNAS USA, 2021 May 11;118(19):e2022940118; Zhang et al., (2019) Molecular Therapy Nucleic Acids, 2019 Jun 7;16:172-185) inhibitors as therapeutics against repeat expansion-induced RNA toxicity in rare neurodegenerative and neuromuscular disorders. We are currently performing lead optimization of our hits and are hosting ongoing discussion with the industry to plan for pre-clinical studies. Approaches employed include biochemical, biophysical, cell biological (including patient iPSC), genetic (Drosophila and mouse models) and structural (including nuclear magnetic resonance, X-ray crystallography and Cryo-electron microscopy/tomography).

1. Koon, A.C.#, Yeung, K.Y.W.#, Wu, Y., Leong, L.I, Cheung, J.T.P., Chen, Z.S., Peng, S.I., Armstrong, N.S., Frank, A.C., Magneron, P., Gomes-Pereira, M., Fung, J.M.S., Bargiela, A., Moreno, N., Poyatos, J., Vilchez, J., Vilchez, J., Huguet, A., Brewer, C.K., Zinter, M., Beck, E.S., Artero, R., Gourdon, G., Budnik, V., Thomson, T., McCabe, B.D. and Chan, H.Y.E.* (2026) Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy. Nat. Commun. 17(1):1005 DOI: 10.1038/s41467-025-67738-w

2. Chen, Z.S., Peng, S.I., Leong, L.I, Gall-Duncan, T., Wong, N.S.J., Li, T.H., Lin, X., Wei, Y., Koon, A.C., Huang, J., Sun, J.K., Turner, C., Tippett, L., Curtis, M.A., Faull, R.L.M., Kwan, K.M., Chow, H.M., Ko, H., Chan, T.F., Pearson, C.E. and Chan, H.Y.E.* (2025) Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5. Nat. Commun. 16(1):3307 DOI: 10.1038/s41467-025-58618-4

3. Chen, Z.S., Ou, M., Taylor, S., Dafinca, R., Peng, S.I., Talbot, K.* and Chan, H.Y.E.* (2023) Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulate Wnt/b-catenin pathway in C9ALS/FTD. Nat. Commun. 14(1):8420 DOI: 10.1038/s41467-023-44215-w

4. An, Y., Chen, Z.S., Chan, H.Y.E.* and Ngo, J.C.K.* (2022) Molecular insights into the interaction of CAG trinucleotide RNA repeats with nucleolin and its implication in polyglutamine diseases. Nucl. Acids Res. 50(13), 7655-7668. DOI: 10.1093/nar/gkac532

5. Peng, S.I., Leong, L.I., Sun, J.K., Chen, Z.S., Chow, H.M. and Chan, H.Y.E.* (2022) A peptide inhibitor that rescues polyglutamine-induced synaptic defects and cell death through suppressing RNA and protein toxicities. Mol. Ther. Nucleic Acids 29, 102-115. DOI: 10.1016/j.omtn.2022.06.004

6. Peng, S., Guo, P., Lin, X., An, Y., Sze, K.H., Lau, M.H.Y., Chen, Z.S., Wang, Q., Li, W., Sun, J.K., Ma, S.Y., Chan, T.F., Lau, K.F., Ngo, J.C.K., Kwan, K.M., Wong, C.H., Lam, S.L., Zimmerman, S.C., Tuccinardi, T., Zuo, Z., Au Yeung, H.Y., Chow, H.M. and Chan, H.Y.E.* (2021) CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration. Proc. Natl. Acad. Sci. USA. 118(19) e2022940118 DOI: 10.1073/pnas.2022940118

7. Zhang, Q., An, Y., Chen, Z.S., Koon, A.C., Lau, K.F., Ngo, J.C.* and Chan, H.Y.E.* (2019) A peptidylic inhibitor for neutralizing r(GGGGCC)exp-associated neurodegeneration in C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia. Mol. Ther. Nucleic Acids 16, 172-185. DOI: 10.1016/j.omtn.2019.02.015

8. Chen, Z.S., Li, L., Peng, S., Chen, F.M., Zhang, Q., An, Y., Lin, X., Li, W., Chan, T.F., Lau, K.F., Ngo, J.C., Wong, W.T., Kwan, K.M. and Chan, H.Y.E.* (2018) Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative diseases. EMBO Rep. 19, e45419 DOI: 10.15252/embr.201745409

9. Tsoi, H., Yu, A.C., Chen, Z.S., Ng, N.K., Chan, A.Y., Yuen, L.Y., Abrigo, J.M., Tsang, S.Y., Tsui, S.K., Tong, T.M., Lo, I.F., Lam, S.T., Mok, V.C, Wong, L.K., Ngo, C.K., Lau, K.F., Chan, T.F.* and Chan, H.Y.E.* (2014) A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia. J. Med. Genet. 51, 590-595. DOI: 10.1136/jmedgenet-2014-102333

10. Tsoi, H., Lau, C.K., Tsang, S.Y., Lau, K.F. and Chan, H.Y.E.* (2012) CAG expansion induces nucleolar stress in polyglutamine diseases. Proc. Natl. Acad. Sci. USA. 109, 13428-13433. DOI: 10.1073/pnas.1204089109