Y. Hwan Kim, PhD
|Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, affecting more than 1% of the population above the age of 65. The disorder is primarily characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain and formation of intraneuronal inclusions called "Lewy bodies" which contain alpha-synuclein as their major protein component. The pathological mechanisms involved in neuropathology associated with PD is largely unknown, however, the A53T mutation of alpha-synuclein causes Lewy body formation and is a well-known genetic PD model.|
|Project 1: Lithium has recently been suggested to have neuroprotective effects in several models of neurodegenerative disease including PD and amyotrophic lateral sclerosis (ALS). We examined the potential use of lithium for reducing abnormal involuntary movements (AIMs) as well as protecting neurons against cell death in MPTP-lesioned mice and MPP+-damaged N27 rat dopaminergic cell line. Chronic lithium administration (0.127% LiCl in food) for 3 weeks was sufficient to effectively reduce AIMs in MPTP-lesioned mice and to suppress MPTP-induced calpain-1 expression. Further, lithium up-regulated the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase (TH) in both N27 cell line and mouse brain including the SNpc and the striatum. We tested the proposed pathways to assess the neuroprotective mechanisms of lithium in PD models. These results suggest the potential use of lithium in combination with other therapeutic compounds such as L-dopa not only as a neuroprotectant, but also for reducing levodopa-induced dyskinesia (LID) and alleviating potential side-effects associated with current treatment for PD.|
|Project 2: Using recently created alpha-synuclein-EGFP transfected N27 rat dopaminergic cell lines, we compare the nuclear and mitochondrial localization rate of wild type (WT) synuclein with that of various mutants of the protein (the familial mutant A53T and two mutants of non-phosphorylated (S129A) and phosphorylated mimic (S129D) at ser-129 to assess how these events may alter subcellular location and further dopaminergic cellular dysfunction. In our preliminary data, we found that serine-129 phosphorylation mimic (S129D) was significantly interrupted in the translocation to nucleus, compared with non-phosphorylation mimic (S129A). In addition, the histone acetyltransferase (HAT) activity in S129D was lower than that in S129A, while the histone deacetylase (HDAC) activity was not different. We hypothesize that the mutation (A53T) and alteration at ser-129 phosphorylation may impact on rates of nuclear localization, thereby affecting histone binding/acetylation and subsequent transcriptional regulation. These mutation/alterations in alpha-synuclein may also induce different protein-protein interactions for mediating protein aggregation or degradation, in addition to impact on localization to the nucleus or the inner mitochondrial membrane and mitochondrial function. These proposed studies will give us insights of the mechanisms involved in subcellular localization and differential protein-protein interactions of different forms of alpha-synuclein (WT, A53T, S129D, and S129A) and how this impacts on neuropathological processes associated with PD via alterations in protein degradation and gene expression or mitochondrial dysfunction.|
|Project 3: Many pesticides including Paraquat and Maneb cause neurodegenerative diseases. Using dopaminergic cell line, we assess neurotoxic effects of commonly used pesticides individually and in combination. We are screening numerous compounds including atrazine, its breakdown product: deethylatrazine (DEA), metolachlor, cyanazine, alachlor, and EPTC individually. The Initial cytotoxicity screen with the exposure of 24-48 hours will be measured in MTT and LDH assays, followed by analyzing their combination toxicity for measuring synergistic effects. Further, we test potential protective effects by compounds such as lithium, curcumin, and Prostandim against oxidative stress caused by those pesticides. These studies will provide us insights of the potential damaging effects by those pesticide combinations and the potential protective effects by those compounds, which are directly relevant to understand sporadic PD pathology in addition to preventing dopaminergic neuronal loss for developing PD clinical therapies.|
|Lab members: Y. Hwan Kim (Principal Investigator, Assistant Professor) Carol Lazzara (MS/Ph.D. student), Kinjal Patel (Lab manager), Undergraduate researchers: Margaret Steward, Nicole Brown, Doug Mullen, Xenia Davis, and Cassio Noso.
Common Lab techniques: Western-blot, qRT-PCR, cell viability assays (MTT & LDH), ELISA, protein activity assays, microarray and immunohistochemistry.
Education and Training (Y. Hwan Kim)
|Korea University, Seoul, S. Korea||BA||Plant Physiology/ Genetic Engineering|
|Korea University, Seoul, S. Korea||MS||Biotechnology|
|University of California, Los Angeles (UCLA)||PhD||Neuroscience|
|Johns Hopkins Medical Institution, Baltimore, MD||Post-Doctoral Fellow||Neuropathology in School of Medicine|
|Buck Institute for Research on Aging, Novato, CA||Sr Post-Doc||Parkinson’s Disease|
Memberships and Awards:
• Lazzara CL, Riley RR, Rane A, Steward M, Andersen JK, and Kim YH -- The combination of lithium and Carbidopa/L-dopa reduces abnormal involuntary movements (AIMs) in MPTP-lesioned mice, mediated by calpain1 inhibition and tyrosine-hydroxylase (TH) up-regulation for Parkinson's disease therapy. Neuropharmacology (in preparation)
• Kim YH, Rane A, Lussier S, and Andersen JK -- Lithium protects against oxidative stress-mediated cell death in alpha-synuclein over-expressing in vitro and in vivo models of Parkinson’s disease. J. Neurosci Res. 2011 Oct, 89(10):1666-75.
• Kim YH, Lussier S, Rane A, Choi SW, and Andersen JK -- Inducible dopaminergic glutathione depletion in an alpha-synuclein transgenic mouse model results in age-related olfactory dysfunction. Neuroscience 2011 Jan, 13;172:379-86.
• Satre D, Kim YH, and Corbitt C -- Androgen receptor location in the Dark-eyed Junco using a probe for in situ hybridization histochemistry generated from zebra finch cDNA. J. Neuroscience Methods 2011 Sept, 30;201(1):180-4.
• Naurin S, Hansson B, Hasselquist D, Kim YH, and Bensch S -- The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds. BMC Genomics 2011 Jan; 14;12(1):37.
• Itoh Y, Replogle K, Kim YH, Wade J, Clayton DF, and Arnold AP -- Sex bias and dosage compensation in the zebra finch versus chicken genomes: general and specialized patterns among birds. Genome Research. 2010 Apr; 20(4):512-8.
• Dragich JM, Kim YH, Arnold AP, Schanen CN -- Differential distribution of the Mecp2 splice variants in the postnatal mouse brain. J Comp Neurol. 2007 Feb 2;501(4):526-542.
• Kim YH, Arnold AP -- Expression of NGF and trkA mRNA in song control and other regions of the zebra finch brain. Neurosci. Lett. 2006 Dec 1;409(2):151-6.
• Kim YH, Peregrine J, Arnold AP -- The distribution of expression of doublecortin (DCX) mRNA and protein in zebra finch brain. Brain Research. 2006 Aug 23;1106(1):189-96.
• Kim YH, Arnold AP -- Distribution and onset of retinaldehyde dehydrogenase (zRalDH) expression in the zebra finch brain: lack of sex difference in HVC and RA at early posthatch ages. J. Neurobiol. 2005 Dec;65(3):260-268 Kim YH, Perlman WR, Arnold AP -- • Expression of androgen receptor mRNA in the zebra finch song system: developmental regulation by estrogen. J Comp Neurol. 2004 Feb 16;469(4):535-47.
• Cole AM, Tahk S, Oren A, Yoshioka D, Kim YH, Park A, Ganz T -- Determinants of Staphylococcus aureus nasal carriage. Clin Diagn Lab Immunol. 2001 Nov;8(6):1064-9.
• Cole AM, Kim YH, Tahk S, Hong T, Weis P, Waring AJ, Ganz T -- Calcitermin, a novel antimicrobial peptide isolated from human airway secretions. FEBS Lett. 2001 Aug 24;504(1-2):5-10.
• Cole AM, Shi J, Ceccarelli A, Kim YH, Park A, Ganz T -- Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. Blood. 2001 Jan 1;97(1):297-304.
• Saldanha CJ, Tuerk MJ, Kim YH, Fernandes AO, Arnold AP, Schlinger BA -- Distribution and regulation of telencephalic aromatase expression in the zebra finch revealed with a specific antibody. J Comp Neurol. 2000 Aug 7;423(4):619-30.
• Cole AM, Wu M, Kim YH, Ganz T -- Microanalysis of antimicrobial properties of human fluids. J Microbiol Methods. 2000 Jul;41(2):135-43.
• Kim YH, Yang JW, Kim CW -- Suspension culture of an antibacterial peptide producing cell line from Bombina orientalis. J Microbiol and Biotech. 1998 8(5):461-465.
Summary of Center-Funded Research
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