About Dr. Yoon-Seong Kim

Elucidate the molecular mechanism underlying the pathogenesis of Parkinson's disease. Current focus is on DNA oxidative damage and its contribution to mutated α-syn through transcriptional mutagenesis.

 

Our studies mainly focus on oxidative stress, epigenetic regulation and their roles in the pathogenesis of Parkinson’s disease (PD) with special emphasis on alpha-synuclein (a-SYN).

 

Research Focus

 

  1. The role of NADPH oxidases (NOXs)-mediated oxidative stress in the pathogenesis of Parkinson’s disease. In addition to mitochondria, we have identified NADPH oxidase 1 (NOX1) as a molecular source of ROS which is responsible for dopaminergic neuronal death. NOX1 is highly expressed in the intestinal epithelium, from where recent accumulating evidence suggests that a-SYN aggregates progressively propagate to the brain parenchyma. Using Nox1 null mice, we are investigating gut microbiome-Nox1 activation-a-SYN pathogenesis axis in PD.
  2. Contribution of transcriptional mutagenesis of oxidative DNA lesions to generating new mutant α-SYN species and aggregation. We have recently discovered that 8-oxo-dG, the most frequent oxidative DNA lesion, can generate mutant a-SYN species by the intriguing mechanism called transcriptional mutagenesis. These mutant a-SYN mRNA species were more frequently observed in the substantia nigra of PD patients compared to normal subjects. We are investigating how these mutant species contribute to the alpha-synucleinopathy.
  3. Pum2-mediated translational regulation of alpha-synuclein mRNA on the outer surface of mitochondria. Interplay between mitochondria and a-SYN has been widely documented yet without clear molecular mechanism. We have found that a-SYN mRNA is localized to the outer surface of mitochondria and its translation is initiated upon stimuli causing mitochondrial ROS. We have identified that Pum2, a translational repressor, binds to the 3’UTR of a-SYN mRNA and it is released upon mitochondrial ROS, allowing translational initiation of a-SYN near mitochondria. We are investigating the role of translational control of a-SYN near mitochondria.
  4. Chromatin landscape and epigenetic regulation of a-SYN in PD. In human, the α-SYN gene (SNCA) contains high CpG rich region around transcription start site. We have found that CpGs in this region of dopaminergic neurons and human brain tissue are largely unmethylated in both control and PD conditions. Histone marks, however, demonstrate significant differences between them with for example much higher H3K4me3 levels in PD, supporting elevated a-SYN levels. To modulate epigenetic marks in a precise target-specific manner, a CRISPR/dCas9-Suntag technique has been developed.

 

Major Techniques Established

 

  1. The CRIPSR/dCas9-Suntag based target-specific epigenetic modifiers. We recently established ten epigenetic modifying enzymes that modulate major histone marks including H3K4me3, H3K27me3, H3K9ac, H3K27ac and DNA methylation using CRISPR/dCas9-Suntag system. This epigenetic tool kit allows target-specific modulations of each genomic loci. In conjunction with sgRNA library spreading over the entire genome, this innovative technique can be applied to the identification of specific genes whose epigenetic modulations are critical for various disease conditions.
  2. Single-molecule fluorescence in situ hybridization (smFISH) with human brain clearing technique. To overcome strong auto-fluorescence from human brain tissue, especially dopaminergic neurons due to neuromelanin, we have established the technique to clear proteins/lipids after RNA-anchoring/gel embedding, enabling clear visualization of a single RNA. Together with the expansion microscope technique, subcellular localization of single RNA molecule can be visualized.
  3. Single-molecule pull down assay to count minute amounts of proteins from human brain. We established this technique to literally count small amount of mutant a-SYN protein contained in postmortem substantia nigra samples. This technique uses TIRF microscope with mathematical image analysis, allowing stoichiometric information of proteins, for example, oligomeric status of a-SYN.

 

Publication Lists

  1. Je, G., Guhathakurta, S., Yun, S. P., Ko, H. S. & Kim, Y. S. (2018). A novel extended form of alpha-synuclein 3’UTR in the human brain. Mol Brain 11, 29.
  2. Je, G. & Kim, Y. S. (2017). Mitochondrial ROS-mediated post-transcriptional regulation of alpha-synuclein through miR-7 and miR-153. Neurosci Lett 661, 132-136.
  3. Je, G., Croop, B., Basu, S., Tang, J., Han, K. Y. & Kim, Y. S. (2017). Endogenous Alpha-Synuclein Protein Analysis from Human Brain Tissues Using Single-Molecule Pull-Down Assay. Anal Chem 89, 13044-13048.
  4. Guhathakurta, S., Evangelista, B. A., Ghosh, S., Basu, S. & Kim, Y. S. (2017). Hypomethylation of intron1 of alpha-synuclein gene does not correlate with Parkinson’s disease. Mol Brain 10, 6.
  5. Guhathakurta, S., Bok, E., Evangelista, B. A. & Kim, Y. S. (2017). Deregulation of alpha-synuclein in Parkinson’s disease: Insight from epigenetic structure and transcriptional regulation of SNCA. Prog Neurobiol.
  6. Basu, S., Adams, L., Guhathakurta, S. & Kim, Y. S. (2017). A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3’end using CRISPR-Cas9 genome editing technique. Sci Rep 8, 45883.
  7. Rocha, S. M., Saraiva, T., Cristovao, A. C., Ferreira, R., Santos, T., Esteves, M., Saraiva, C., Je, G., Cortes, L., Valero, J., Alves, G., Klibanov, A., Kim, Y. S. & Bernardino, L. (2016). Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation. J Neuroinflammation 13, 137.
  8. Bae, Y. S., Choi, S., Park, J. J., Joo, J. H., Cui, M., Cho, H., Lee, W. J. & Lee, S. H. (2016). Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors. Bioorg Med Chem.
  9. Nam, J. H., Park, E. S., Won, S. Y., Lee, Y. A., Kim, K. I., Jeong, J. Y., Baek, J. Y., Cho, E. J., Jin, M., Chung, Y. C., Lee, B. D., Kim, S. H., Kim, E. G., Byun, K., Lee, B., Woo, D. H., Lee, C. J., Kim, S. R., Bok, E., Kim, Y. S., Ahn, T. B., Ko, H. W., Brahmachari, S., Pletinkova, O., Troconso, J. C., Dawson, V. L., Dawson, T. M. & Jin, B. K. (2015). TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF. Brain.
  10. Choi, D. H., Kim, J. H., Lee, K. H., Kim, H. Y., Kim, Y. S., Choi, W. S. & Lee, J. (2015). Role of neuronal NADPH oxidase 1 in the peri-infarct regions after stroke. PLoS One 10, e0116814.
  11. Basu, S., Je, G. & Kim, Y. S. (2015). Transcriptional mutagenesis by 8-oxodG in alpha-synuclein aggregation and the pathogenesis of Parkinson’s disease. Exp Mol Med 47, e179.
  12. Ha, J. Y., Kim, J. S., Kang, Y. H., Bok, E., Kim, Y. S. & Son, J. H. (2014). Tnfaip8 l1/Oxi-beta binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson’s disease model. J Neurochem.
  13. Choi, D. H., Lee, K. H., Kim, J. H., Seo, J. H., Kim, H. Y., Shin, C. Y., Han, J. S., Han, S. H., Kim, Y. S. & Lee, J. (2014). NADPH Oxidase 1, a Novel Molecular Source of ROS in Hippocampal Neuronal Death in Vascular Dementia. Antioxid Redox Signal.
  14. Choi, D. H., Kim, J. H., Seo, J. H., Lee, J., Choi, W. S. & Kim, Y. S. (2014). Matrix metalloproteinase-3 causes dopaminergic neuronal death through Nox1-regenerated oxidative stress. PLoS One 9, e115954.
  15. Lee, K. W., Im, J. Y., Woo, J. M., Grosso, H., Kim, Y. S., Cristovao, A. C., Sonsalla, P. K., Schuster, D. S., Jalbut, M. M., Fernandez, J. R., Voronkov, M., Junn, E., Braithwaite, S. P., Stock, J. B. & Mouradian, M. M. (2013). Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson’s disease. Neurotherapeutics 10, 143-53.
  16. Cristovao, A. C., Barata, J., Je, G. & Kim, Y. S. (2013). PKCdelta mediates paraquat-induced Nox1 expression in dopaminergic neurons. Biochem Biophys Res Commun.
  17. Chung, Y. C., Kim, Y. S., Bok, E., Yune, T. Y., Maeng, S. & Jin, B. K. (2013). MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson’s disease. Mediators Inflamm 2013, 370526.
  18. Campos, F. L., Carvalho, M. M., Cristovao, A. C., Je, G., Baltazar, G., Salgado, A. J., Kim, Y. S. & Sousa, N. (2013). Rodent models of Parkinson’s disease: beyond the motor symptomatology. Front Behav Neurosci 7, 175.
  19. Kim, Y. S. & Joh, T. H. (2012). Matrix Metalloproteinases, New Insights into the Understanding of Neurodegenerative Disorders. Biomol Ther (Seoul) 20, 133-143.
  20. Cristovao, A. C., Guhathakurta, S., Bok, E., Je, G., Yoo, S. D., Choi, D. H. & Kim, Y. S. (2012). NADPH oxidase 1 mediates alpha-synucleinopathy in Parkinson’s disease. J Neurosci 32, 14465-77.
  21. Choi, D. H., Cristovao, A. C., Guhathakurta, S., Lee, J., Joh, T. H., Beal, M. F. & Kim, Y. S. (2012). NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson’s disease. Antioxid Redox Signal 16, 1033-45.
  22. Chaturvedi, R. K., Hennessey, T., Johri, A., Tiwari, S. K., Mishra, D., Agarwal, S., Kim, Y. S. & Beal, M. F. (2012). Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntington’s disease. Hum Mol Genet 21, 3474-88.
  23. Huh, S. H., Chung, Y. C., Piao, Y., Jin, M. Y., Son, H. J., Yoon, N. S., Hong, J. Y., Pak, Y. K., Kim, Y. S., Hong, J. K., Hwang, O. & Jin, B. K. (2011). Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson’s disease. J Immunol 187, 960-9.
  24. Chung, Y. C., Kim, S. R., Park, J. Y., Chung, E. S., Park, K. W., Won, S. Y., Bok, E., Jin, M., Park, E. S., Yoon, S. H., Ko, H. W., Kim, Y. S. & Jin, B. K. (2011). Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology 60, 963-74.
  25. Chung, Y. C., Bok, E., Huh, S. H., Park, J. Y., Yoon, S. H., Kim, S. R., Kim, Y. S., Maeng, S., Park, S. H. & Jin, B. K. (2011). Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. J Immunol 187, 6508-17.
  26. Choi, D. H., Kim, Y. J., Kim, Y. G., Joh, T. H., Beal, M. F. & Kim, Y. S. (2011). Role of matrix metalloproteinase 3-mediated alpha-synuclein cleavage in dopaminergic cell death. J Biol Chem 286, 14168-77.
  27. Choi, D. H., Hwang, O., Lee, K. H., Lee, J., Beal, M. F. & Kim, Y. S. (2011). DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death. Antioxid Redox Signal 14, 2137-50.
  28. Cristovao, A. C., Choi, D. H., Baltazar, G., Beal, M. F. & Kim, Y. S. (2009). The role of NADPH oxidase 1-derived reactive oxygen species in paraquat-mediated dopaminergic cell death. Antioxid Redox Signal 11, 2105-18.