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Molecular Mechanisms of Parkinson's Disease
Our major research goal is to understand the molecular mechanisms driving the loss of brain cells in Parkinson’s disease patients. A clear understanding of both the normal biology and the pathobiology of gene products associated with PD is necessary to gain important insight into the molecular mechanisms and pathways underlying neurodegeneration in PD. Such research has the potential to elucidate novel therapeutic strategies for treatment or prevention of parkinsonian type diseases. To achieve these goals, we utilize a combination of genetically modified animal models to study disease pathogenesis in vivo and neurobiological approaches in vitro. Ongoing projects in the lab include:
- Mechanisms of neurodegeneration in human alpha-synuclein transgenic mice
- The interaction between Glucocerebrosidase (GBA) and Parkinson’s disease
- Identification and characterization of important pathophysiologic substrates of parkin that link parkin function to familial and sporadic PD.
1. Mechanisms of neurodegeneration in alpha-synuclein transgenic mice
Mechanisms of neurodegeneration in alpha-synuclein transgenic mice: Alpha-synuclein is directly implicated in PD pathogenesis and other alpha-synucleinopathies. We are using an alpha-synuclein transgenic mouse model to define in vivo pathogenic and neurodegenerative mechanisms that are relevant to PD. Mitochondrial abnormalities and oxidative stress are also implicated in the pathogenesis of PD and other alpha-synucleinopathies. We are currently studying neurodegenerative disease in transgenic mice to determine if it is associated with oxidative stress resulting from mitochondrial abnormalities.
2. The interaction between Glucocerebrosidase (GBA) and Parkinson’s disease
The interaction between Glucocerebrosidase (GBA) and Parkinson’s disease: We are currently focusing on GBA genes that have been identified as the most prevalent genetic risk factor in PD, and are examining their physiologic/pathophysiologic roles in vivo.
3. Identification and characterization of important pathophysiologic substrates of parkin that link parkin function to familial and sporadic PD
Identification and characterization of important pathophysiologic substrates of parkin that link parkin function to familial and sporadic PD: In collaboration with the Dawson lab, we have made substantial contributions towards understanding parkin function. Recent discoveries include the identification of a posttranslational modification that impairs parkin function, and substrates such as AIMP2, FBP1 and PARIS (ZNF746). We are continuing to identify and characterize new parkin substrates that could play a role in the decrease of SN dopaminergic neurons in patients with parkin mutations.
Our work is supported by a grant from the NINDS (P50 NS38377)
PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease
Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM.
Cell. 2011; 144(5): 689-702.
Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function
Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM.
Proc. Natl. Acad. Sci. U.S.A. 2010; 107(38): 16691-16696.
Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease
Lee BD, Shin JH, Vankampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM.
Nat Medicine. 2010; 16(9): 998-1000.
Genetic animal models of Parkinson's disease
Dawson TM, Ko HS, Dawson VL.
Neuron. 2010; 66(5):646-661.
PINK1 dependent recruitment of Parkin to mitochondria in mitophagy
Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrané J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S.
Proc. Natl. Acad. Sci. U.S.A. 2009; 107(1): 378-383.
S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease
Tsang AH, Lee YI, Ko HS, Savitt JM, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Chung KK.
Proc. Natl. Acad. Sci. U.S.A. 2009; 106(12): 4900-4905.
CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity
Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, Patterson C, Petrucelli L, Dawson TM, Dawson VL.
Proc. Natl. Acad. Sci. U.S.A. 2009; 106 (8): 2897-2902.
Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases
Tan JM, Wong ES, Kirkpatrick DS, Pletnikova O, Ko HS, Tay SP, Ho MW, Troncoso J, Gygi SP, Lee MK, Dawson VL, Dawson TM, Lim KL.
Human Molecular Genetics. 2008; 17(3): 431-439.
DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase
Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL.
Proc. Natl. Acad. Sci. U.S.A. 2007; 104(37): 14807-14812.
Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations
Wong ES, Tan JM, Wang C, Zhang Z, Tay SP, Zaiden N, Ko HS, Dawson VL, Dawson TM, Lim KL.
The Journal of Biological Chemistry. 2007; 282(16): 12310-12318.
Identification of far up stream element binding protein-1 as an authentic parkin substrate
Ko HS, Kim SW, Sriram SR, Dawson VL, and Dawson TM.
The Journal of Biological Chemistry. 2006; 281(24): 16193-16196.
Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin’s protective function
Wang C, Ko HS, Thomas B, Tsang F, Tay SP, Chew KCM, Michelle Ho WL, Lim TM, Soong TW, Dawson VL, Dawson TM, Lim KL.
Human Molecular Genetics. 2005; 14(24): 3885-3897.
Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death
Ko HS, von Coelln R, Sriram SR, Kim SW, Chung KK, Pletnikova O, Troncoso J, Johnson B, Saffary R, Goh EL, Song H, Park BJ, Kim MJ, Kim S, Dawson VL, Dawson TM.
The Journal of Neuroscience. 2005; 25(35): 7968-7978.
Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin
Sriram SR, Li X, Ko HS, Chung KK, Wong E, Lim KL, Dawson VL, Dawson TM.
Human Molecular Genetics. 2005; 14(17): 2571-2586.
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