Mechanism of motor response complications in Parkinson’s disease

 One area of investigative focus is the mechanisms underlying the limitations of the current symptomatic treatment in PD.  Dopaminergic replacement therapy is one of the most successful examples of symptomatic treatment for neurodegenerative disorders.  However, patients with advanced PD suffer from motor response complications to the therapy.  To understand the mechanism underlying the development of motor response complications, we developed mouse models of L-DOPA-induced dyskinesia and wearing-off.  Using the mouse models, we are investigating the molecular mechanism underlying this aberrant plasticity response.  The role of NMDA receptor changes and alterations in the cellular signaling pathways leading to these changes are investigated.  Specific anatomical structures that are important in mediating these changes are also defined and therapeutic strategies are explored. 

 Mechanism of dopaminergic neuronal degeneration in Parkinson’s disease

The second area of interest is the pathogenesis of PD.  The central aspect of PD pathogenesis is the degeneration of brain stem nuclei with predilection to dopaminergic neurons in the substantia nigra pars compacta (SNpc).  Both environmental and genetic factors are suspected to play a role in the pathogenesis.  We are currently studying the functions of two genes associated with recessive forms of PD, DJ-1 and PINK1 (PTEN-induced putative kinase 1). We focus on their role in mitochondrial function, oxidative stress and protein processing.  We also study their interaction with potential intrinsic vulnerability factors in SNpc neurons and with environmental toxins so that we may gain understanding of the common mechanisms of dopaminergic neuronal degeneration in both sporadic and genetic forms of PD.

For further information of clinical activities and research, see the description in Department of Neurology and Parkinson's Disease and Movement Disorders Center.
 

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Chang JW, Wachtel SR, Young D, Kang UJ. Biochemical and anatomical characterization of forepaw adjusting steps in a rat model of Parkinsons disease: studies on medial forebrain bundle and striatal lesions. Neuroscience 1999;88:617-628. 

Lee WY, Chang JW, Nemeth NL, Kang UJ. Vesicular monoamine transporter-2 and aromatic L-amino acid decarboxylase enhance dopamine delivery following L-DOPA administration in parkinsonian rats. J Neurosci1999;19:3266-3274.

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Chang JW, Lee WY, Milstien S, Kang UJ. A site-specific mutation of tyrosine hydroxylase reduces feedback inhibition by dopamine in genetically modified cells grafted in parkinsonian rats.  J Neurochem 2002;83:141-149.

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Lee EA, Kim YS, Lee WY, Kang UJ.  The effects of chronic L-DOPA therapy on pharmacodynamic parameters in a rat model of motor response fluctuations. Exp Neurol. 2003;184(1):304-12.

Kweon GR, Marks JD, Krencik R, Leung EH, Hyland K, Schumacker PT, Kang UJ.  Distinct mechanisms of neurodegeneration induced by chronic complex I inhibitiion in dopaminergic and non-dopaminergic cells. J Biol Chem 2004;279(50):51783-51792.

Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Carvey PM, Ling Z, Kang UJ, Zhuang X.  Dopaminergic dysfunction and age-dependent motor deficits in DJ-1 null mice.  J Biol Chem 2005;280(22):21481-26.