Neurodegeneration Research Laboratory

​

Kah-Leong Lim, Ph. D

Visiting Lead Scientist, National Neuroscience Institute
Associate Professor (Joint - 20% FTE), Dept. of Physiology, National University of Singapore
Associate Professor (Regular Rank - Honorary), Duke-NUS Medical School

Contact Information

Neurodegeneration Research Laboratory
National Neuroscience Institute
11 Jalan Tan Tock Seng, Singapore 308433
Tel: (65) 6357 7520 (Office) / (65) 6357 7632 (Lab)
Fax:(65) 6256 9178

The Team

• Ms Eugenia TE Hong, B.Sc. (Laboratory Manager)
• Dr Chai Chou, Ph.D. (Postdoctoral Scientists)
• Dr Grace Lim Gui Yin, Ph.D. (Postdoctoral Scientists)
• Dr Zhang Chengwu, Ph.D. (Postdoctoral Scientists)
• Ms Adeline Henry Basil, B.Sc. (Hons) (Research Assistants)
• Ms Geraldine Goh Wan Ying, B.Sc. (Hons) (Research Assistants)
• Ms Hang Liting, B.Sc. (Hons) (NGS Ph.D. Scholar) (Postgraduate Students)
• Ms Chan Hui Ying, B.Sc. (Hons) (NGS Ph.D. Scholar) (Postgraduate Students)

Overview of Laboratory

The long term primary goal of my lab is to elucidate the molecular events underlying Parkinson Disease (PD), with the view to develop novel therapies aimed at effectively treating the disease. To realise this goal progressively, our research work focuses on achieving the following inter-related objectives:

1. MECHANISMS – To identify and characterise key players/events that contribute to PD pathogenesis
2. MODELS – To generate reliable preclinical models of PD that would facilitate drug discovery efforts
3. MARKERS – To generate selective biomarker probes for disease diagnosis and monitoring
4. MEDICINE – To develop therapeutic strategies based on the knowledge gleaned from our research work

Our other interest is to explore the relatively poorly characterised but intriguing relationship between PD and cancer. This is a novel angle that we have taken, which we believe might shed important insights into the (paradoxically) shared mechanism that underlies the opposite cellular fates of the two seemingly disparate diseases. We are collaborating with A/Prof Ang Beng Ti and Dr Carol Tang from the Neuro-oncology Program to address this.

Reversing PD: https://www.youtube.com/watch?v=G6miix6WH4w

Selected Publications

Parkinson & Related Neurodegenerative Diseases

1. Nucifora, F.C., Nucifora, L.G., Ng, C.H., Arbez, N., Guo, Y., Roby, E., Shani, V., Engelender, S., Wei, D., Wang, X.F., Li, T., Moore DJ, Pletnikova, O., Troncoso, J., Sawa, A., Dawson, T.M., Smith, W., Lim, K.L., Ross, C.A. (2016) Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nature Communications 7: 11792.
2. Lim, G.G., Chua, D.S.K., Basil, A.H., Chan, H.Y., Chai, C., Arumugam, T., Lim, K.L. (2015) Cytosolic PTEN-induced putative kinase 1 is stabilized by NF-κB pathway and promotes non-selective mitophagy Journal of Biological Chemistry 290(27):16882-93.
3. Li, L., Zhang C.W., P., Chen G.Y.J., Zhu, B., Y.W., Chai. C., Xu, Q., Tan, E.K., Kung, S.K.P., Lim, K.L.*, Yao, S.Q.* (2014) A Two-Photon Small Molecule Enzymatic Probe for Specific and Sensitive Detection of Monoamine Oxidase B Activity in Parkinson’s Disease Models. Nature Communications 13;5:3276 (*co-corresponding).
4. Haskin, J., Szargel, R., Shani, V., Mekies, L., Roth, R., Lim, G.G., Lim, K.L., Bandopadhyay, R., Wolosker, H., Engelender, S. (2013) AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson’s disease. Human Molecular Genetics, 22:2083-96.
5. Ng, C.H., Guan, M.S.H., Koh, C., Ouyang, X, Yu, F., Tan, E.K., O’Neill, S., Zhang, X., Chung, J., Lim, K.L. (2012) AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease. Journal of Neuroscience, 32:14311–14317.
6. Lee, JY, Nagano, Y, Taylor, J.P, Lim, K.L., Yao, TP (2010) Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation and HDAC6-dependent mitophagy. Journal of Cell Biology, 189, 671-9.
7. Ng, C.H., Mok, Z.X.S., Koh, C., Ouyang, X., Fivaz, M.L., Tan, E.K., Dawson, V.L., Dawson T.M., Yu, F., and Lim, K.L. (2009) Parkin Protects Against LRRK2 G2019S Mutant-induced Dopaminergic Neurodegeneration in Drosophila Journal of Neuroscience, 29, 11257-11262.
8. Wong E.S.P., Tan, M.M.J., Soong, W.E., Hussein, K., Nukina, N., Dawson, V.L., Dawson T.M., Cuervo, A.M., Lim, K.L. (2008) Autophagy-mediated clearance of aggresome-like inclusions is not a universal phenomenon Human Molecular Genetics., 17, 2570-2582.
9. Tan, M.M.J., Wong E.S.P, Pletnikova, O, Kirkpatrick, D.S., Ko, H., Ho, M.W.L., Tay, S.P., Troncoso, J., Gygi, S.P., Lee, M.K., Dawson, V.L., Dawson T.M., Lim, K.L. (2008) Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Human Molecular Genetics., 17, 431-439.
10. Wang C., Lu, R., Ouyang X., Ho W.L.M., Chia, W., Yu, F., Lim, K.L. (2007) Drosophila Overexpressing Parkin missense mutants exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. Journal of Neuroscience 27, 8563-70.
11. Wang C., Ko, H.S., Thomas, B., Tsang, F., Tay, S.P., Chew, K.C.M., Ho W.L.M., Lim T.M., Soong, T.W., Pletnikova, P., Troncoso, J., Dawson, V.L., Dawson T.M., Lim, K.L. (2005). Stress-induced Alteration in Parkin Solubility Promotes Parkin Aggregation and Compromises Parkin’s Protective Function. Human Molecular Genetics 14, 3885-3897.
12. Lim, K.L., Chew C.M.K., Tan, M.M. J., Wang C., Chung, K.K.K., Zhang, Y., Tanaka Y., Smith, W.L., Engelender, S., Ross, C.A., Dawson, V.L. and Dawson, T.M (2005). Parkin mediates non-classical, proteasomal-independent, ubiquitination of Synphilin-1: Implications for Lewy Body formation. Journal of Neuroscience 25, 2002-2009

Cancer

1. Chong, Y.K., Sandanarai, E., Koh, L.W.H., Thangaveloo, M, Tan, M.S.Y., Koh, G.R., Toh, T.B., Lim, G.G., Holbrook, J.D., Kon, O.L., Nadarajah, M., Ng, I., Ng, W.H., Tan, N.S., Lim, K.L., Tang, C., Ang, B.T. (2016) ST3GAL-1-associated transcriptomic program in glioblastoma tumor growth, invasion and prognosis. Journal of the National Cancer Institute 108(2): djv326.
2. Yeo, W.S., Ng, F.S.L., Chai, C., Tan, JMM, Koh, G., Chong, Y.K., Koh, L.W.H., Foong, C.S.F., Sandanaraj, E., Holbrook, J.D., Ang, B.T., Takahashi, R., Tang, C., Lim, K.L. (2012) Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival. Cancer Research 72 (10); 2543–53.
3. Tay, S.P., Yeo, W.S., Chai, C., Chua, P.J., Tan, H.M., Ang, A.X.Y., Yip, D.L.H., Sung J.X., Tan, P.Y., Bay, B.H., Wong, S.H., Tang, C., Tan, J.M.M., Lim, K.L. (2010) Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. J. Biol. Chem. 285, 29231-8
4. Iglesia, N., Konopka, G., Lim, K.L., Nutt, C.L., Bromberg, J.F., Frank, D.A., Mischel, P.S., Louis, D.N., Bonni, A. (2008) Deregulation of a STAT3-IL8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. Journal of Neuroscience, 28, 5870-5878