萝莉社

• Ph.D., Georgia Institute of Technology, 1986

Environmental toxins and Parkinson鈥檚 disease

Although the exact cause(s) of dopaminergic cell death in Parkinson's disease (PD) is not understood, the commonly accepted view is that the exposure to environmental toxins may be a major cause of PD, especially in individuals with cumulative defects in pathways associated with handling of oxidative stress, mitochondrial function, calcium homeostasis, and the ubiquitin proteasome system. The discovery that 1-methyl-4-phenylpyridinium (MPP⁺) selectively destroys dopaminergic neurons and causes PD symptoms in humans and other mammals has strengthened the environmental hypothesis of PD. Therefore, MPP⁺ has been extensively used to model the environmental causes of PD. The current model for the selective dopaminergic toxicity of MPP⁺ is centered on the specific cellular uptake into dopaminergic cells through the plasma membrane dopamine transporter (DAT) , complex I inhibition leading to ATP depletion, increased reactive oxygen species (ROS) production, and finally apoptotic cell death. However, we have shown that MPP⁺ is taken up not only into dopaminergic cells, but also into various other cells, including liver cells, through various other transporters with high efficiency. Thus, the selective dopaminergic toxicity of MPP⁺ could not be due to the specific uptake into dopaminergic cells through DAT. The focus of current research in my lab is to determine the molecular causes of specific degeneration of the dopaminergic system in PD. Specifically we are interested in:

• Identification of environmental causes and mechanisms of dopaminergic degeneration in PD.
• Determination of the role of Ca²⁺ in mitochondrial accumulation and toxicity of Parkinsonian toxins.
• Determination of the role of catecholamines in the inherent vulnerability of dopaminergic neurons towards mitochondrial toxins.
• Answering the question 鈥淒oes intracellular acidosis mediated TH activation play a role in selective dopaminergic cell death in PD and other neurodegenerative diseases?鈥�

• CHEM 212: General Chemistry II
• CHEM 661: Principles of Biochemistry
• CHEM 662: Biochemistry I
• CHEM 663: Biochemistry II
• CHEM 664: Biochemistry Laboratory

1. Kadigamuwa, C. C., Mapa, S. T., Wimalasena, K. 鈥淟ipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP+鈥� Chem. Res. Toxicol. (ACS), 2016, 28, 1468-1479.
2. Wimalasena, N. K., Viet, Q. L., Wimalasena, K., Schreiber, S. L., Karmacharya, R. 鈥淕ene Expression-Based Screen for Parkinson鈥檚 Disease Identifies GW8510 as a Neuroprotective Agent鈥� ACS Chem. Neurosci, 2016, 7, 857-863
3. Freyberg, Z., Sonders, M., Aguilar, J., Hiranita, T., Karam, C., Flores, J., Pizzo, A., Zhang, Y., Farino, Z., Chen, A., Martin, C., Kopajtic, T., Fei, H., Hu, G., Lin, Y-Y., Mosharov, E., McCabe, B., Freyberg, R., Wimalasena, K., Hsin, L-W., Sames,D., Krantz, D., Katz, J., Sulzer, D., Javitch, J." Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain" Nature Communications 2016, 7, Article # 10652, 1-15.
4. Wimalasena, K. 鈥淭he inherent high vulnerability of dopaminergic neurons towards mitochondrial toxins may contribute to the etiology of Parkinson鈥檚 disease (PD)鈥� Neural Regeneration Research 2016, 11, 246-247 Invited Perspective.
5. Kadigamuwa, C. C., Le, V. Q., Wimalasena, K. 鈥� 2,2- and 4, 4-Cyanines are transporter independent in vivo dopaminergic toxins with the specificity and mechanism of toxicity similar to MPP+鈥� J. Neurochemistry, 2015, 135, 755-767.
6. Wimalasena, K. 鈥淰esicular monoamine transporters: Structure/Function and Pharmacology鈥� Invited Review Medicinal Research Reviews 2011, 31, 483-519 (Invited Review).
7. Wimalasena, D. S., Perera, R. P., Heyen, B. J., Wimalasena , K. 鈥淰esicular Monoamine Transporter Substrate/Inhibitor activity of MPP+ Derivatives: A Structure-Activity Study" J. Med. Chem. 2008, 51, 760-768.
8. Samms, W. C., Perera, R. P., Wimalasena, D. S., Wimalasena, K. 鈥淧erturbation of Dopamine Metabolism by 3-Amino-2-(4'-Halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death鈥� Mol. Pharmacol. 2007, 72, 744-752.
9. Wimalasena, D. S., Wiese, T. J., Wimalasena, K. 鈥淐opper Ions Disrupt Dopamine Metabolism via Inhibition of V-H+-ATPase: A Possible Contributing Factor to Neurotoxicity J. Neurochem. 2007, 101, 313-326.