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

BIOGRAPHY

• Assistant Professor (Joint), Duke-NUS Graduate Medical School, Singapore (2007 - date)
• Research Scientist, NNI Parkinson's disease and Movement Disorders Center, National Parkinson Foundation (USA) International Center of Excellence (2006 - date)
• Group leader (adjunct), OLS Neurobiology Group, National University of Singapore, Singapore (2003 - date)
• Assistant Professor (Adjunct), Dept of Biological Sciences,
  National University of Singapore, Singapore (2003 - date)
• 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)

RESEARCH AREAS

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., 2007 Hum. Mol. Genet.). Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.


REPRESENTATIVE PUBLICATIONS

• 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, in press
  
  
• 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 Jeanne Tan, Ph.D (SMF Fellow)
• Dr Ng Chee Hoe, Ph.D (SMF Fellow)
• Ms Katherine Chew, B.Sc.Hons (Grad. Student)
• Mr Calvin Yeo, M.Sc. (SMF-supported Grad.Student)
• Ms Tay Shiam Peng, B.Sc. (Snr Research Assistant)
• Ms Eugenia Hong, B.Sc. (Lab Manager) 
• Mr Shaun Mok Zhi Xiong, Dip. (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

• Dr Rejko Krueger, University of Tuebingen, Tuebingen, GERMANY
   
• Dr. Simone Engelender, Technion Israel Institute of Technology, ISRAEL