Lim, Kah Leong

Research Interests:

I. Molecular mechanisms of neurodegeneration in Parkinson's disease

To develop better treatments for PD, it is necessary to clarify the molecular pathogenesis of the disease, information of which would allow the identification and therapeutic exploitation of key molecules involved in the pathogenic process. The recent identification of PD-linked genes has provided tremendous opportunities for us to gain insights into the otherwise enigmatic pathogenic events surrounding the more common sporadic PD cases. A main part of our current research thus focuses on the functional characterization of important PD-linked genes such as parkin and LRRK2 (which together account for the majority of genetic-linked PD cases). Through this, we hope to clarify the molecular sequence of events underlying neurodegeneration in PD.

II. Biogenesis and clearance of protein inclusions associated with PD and other neurodegenerative diseases

Although the presence of protein inclusions represents an almost invariant pathological hallmark of neurodegenerative diseases including PD, the mechanisms underlying their biogenesis and clearance remain unclear. 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-proteolytic 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.). Currently, our efforts are directed towards elucidating the precise mechanism governing autophagic clearance of inclusion cobwebs in the brain. Harnessing the autophagic pathway could offer innovative approaches in the treatment of PD and other neurodegenerative disorders.

Selected Publications:

Tan, M.M.J., Wong E.S.P., and Lim, K.L. (2009) Protein misfolding and aggregation in Parkinson's disease. Antioxidants & Redox Signaling (Forum Issue on Parkinson's disease) Epub Feb 25, 2009.

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

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, 8563-70

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

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 27 (4), 524-9

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