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LIM Kah Leong, PhD Head Neurodegeneration Research Laboratory National Neuroscience Institute 11 Jalan Tan Tock Seng Singapore 308433 Tel: (65) 6357-7520 Fax: (65) 6256-9178 Email : kah_leong_lim@nni.com.sg |
- Senior Research Scientist, National Neuroscience Institute, Singapore
- Associate Professor (Joint), Duke-NUS Graduate Medical School, Singapore
- Associate Professor (Joint), Department of Physiology, National University of Singapore, Singapore
- Principal Investigator (Adjunct), Neurobiology/Ageing Program, Life Sciences Institute, National University of Singapore, Singapore
EDUCATION/TRAINING
- Postdoctoral Fellowship (Neurology), The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (2001-2002)
- Postdoctoral Fellowship (Pathology), Harvard Medical School, Boston, Massachusetts, USA (2000-2001)
- Ph.D. Institute of Molecular and Cell Biology, Singapore (1994-1999)
Molecular Mechanisms of Neurodegeneration in Parkinson's disease (PD)
To develop better treatments for PD, it is necessary to identify and therapeutically exploit key molecules involved in the pathogenic process. Currently, our research work focuses on two important PD-linked genes, parkin and LRRK2. Mutations in parkin cause autosomal recessive PD and currently represent the most common cause of familial early-onset PD. On the other hand, LRRK2 mutations cause autosomal dominant PD and account for 5-6% of patients with familial PD and an unprecedented 1-3% prevalence in sporadic PD. Insights into how parkin and LRRK2 dysfunction result in dopaminergic neuronal degeneration could suggest novel therapeutic strategies to intervene disease progression.
Biogenesis & clearance of protein inclusions
We are also interested to learn about the mechanisms, dynamics and relevance of protein inclusions formation in PD and other neurodegenerative diseases. We hypothesized that the formation of protein inclusions may represent an attempt by the cell to prevent a proteasome "overdrive" (as such prolonging its survival) in times of chronic stress (Lim et al., 2006 Neurobiol. Aging). Supporting this, we recently identified the non-classic K63 polyubiquitin as a signal that facilitates the biogenesis of inclusions (Lim et al., 2005 J. Neurosci.) as well as their clearance by autophagy (Tan et al., 2008 Hum. Mol. Genet.; Tan et al., 2008 Autophagy). Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.
- Lim, K.L
., and Lim, G.G. (2010) K63-linked ubiquitination and neurodegeneration Neurobiology of disease, in press
- 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
- 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
Tan, M.M.J., Wong E.S.P, Lim, K.L. (2009) Protein misfolding and aggregation in Parkinson’s disease Antioxidants & Redox Signaling (Forum Issue on Parkinson’s disease), 11(9), 2119-2134
- 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, 17,2570-82
- Tan, M.M.J., Wong E.S.P, Dawson, V.L., Dawson T.M., Lim, K.L. (2008)
Lysine 63 polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy Autophagy, 4(2), 251-253
- 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
- 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, 8563-8570
- Wong E.S.P., Tan, M.M.J, Wang C, Zhang Z, Tay, SP, Zaiden, N, Ko, H. Dawson, V.L., Dawson T.M., Lim K.L.(2007)
Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations J. Biol.Chem., 282, 12310-12318
- West, A.B., Moore, D.J., Choi, C., Andrabi, S., Li, X., Dikeman, D, Biskup, S., Zhang, Z., Lim, K.L., Dawson, V.L., Dawson, T.M. (2007)
Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
Human Molecular Genetics, 16, 223-232
- Lim, K.L., Dawson, V.L. and Dawson T.M. (2006)
Parkin-mediated lysine 63-linked polyubiquitination: A link to protein inclusions formation in Parkinson’s and other conformational diseases? Neurobiology of Aging 14, 3885 - 3897
- 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
- Wang C., Tan, M.M. J., Ho W.L.M., Zaiden N., Chew L.C.C., Eng P.W., Wong S.H., Lim T.M., Dawson T.M., Lim, K.L. (2005)
Alterations in the Solubility and Intracellular Localization of Parkin by Several Familial Parkinson’s Disease-linked Point Mutations Journal of Neurochemistry, 93, 422-431
- 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
- Von Coelln, R., Thomas, B., Savitt, J.M., Lim, K.L., Sasaki, M., Hess, E., Dawson, V.L. and Dawson, T.M. (2004)
Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc. Natl. Acad. Sci. 101, 10744-49
- Chung, K.K.K., Zhang, Y., Lim, K.L. et al. (2001)
Parkin ubiqutinates the a -synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson’s disease. Nature Medicine. 7, 1144-1150
TEAM MEMBERS
- Dr Ng Chee Hoe, Ph.D (SMF Fellow)
- Dr Zhang Chengwu, Ph.D
- Dr Kua Hui Yi, Ph.D
- Ms Eugenia Hong, B.Sc. (Lab Manager)
- Ms Tay Shiam Peng, B.Sc. (Snr Research Assistant)
- Ms Cherlyn Koh, B.Sc (Snr Research Assistant)
- Ms Tan Hui Mei, B.Sc. (Snr Research Assistant)
- Mr Calvin Yeo, M.Sc. (SMF-supported Grad.Student)
- Ms Grace Lim, B.Sc. (Hons) (SMF-supported Grad Student)
- The late Mr Shaun Mok Zhi Xiong, B.Sc. (Snr Research Assistant)
COLLABORATORS
- Professors Ted Dawson and Valina Dawson,The Johns Hopkins University School of Medicine, Baltimore, USA
- Assoc. Prof. Ana Maria Cuervo, Albert Einstein College of Medicine, USA.
- Professor Nobuyuki Nukina, RIKEN Brain Science Institute, JAPAN
- Professor Keiji Tanaka and Dr. Noriyuki Matsuda, Tokyo Metropolitan Institute of Science, JAPAN
- Dr Rejko Krueger, University of Tuebingen, Tuebingen, GERMANY
- Dr. Simone Engelender, Technion Israel Institute of Technology, ISRAEL
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