Research Article Dopamine Cytotoxicity Involves Both Oxidative and Nonoxidative Pathways in SH-SY5Y Cells: Potential Role of Alpha-Synuclein Overexpression and Proteasomal Inhibition in the Etiopathogenesis of Parkinson’s Disease Kalpita Banerjee, 1,2 Soumyabrata Munshi, 1,3 Oishimaya Sen, 1 Vishmadeb Pramanik, 4 Tapasi Roy Mukherjee, 1,5 and Sasanka Chakrabarti 1 1 Department of Biochemistry, Institute of Post-Graduate Medical Education & Research, 244B, Acharya J. C. Bose Road, Kolkata 700020, India 2 Department of Neuroscience, Burke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA 3 Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA 4 DNA Laboratory, Anthropological Survey of India, 27, J. N. Road, Kolkata 700016, India 5 National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Kolkata 700010, India Correspondence should be addressed to Sasanka Chakrabarti; profschakrabarti95@gmail.com Received 6 November 2013; Revised 19 February 2014; Accepted 25 February 2014; Published 2 April 2014 Academic Editor: Nobutaka Hattori Copyright © 2014 Kalpita Banerjee et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. he cytotoxic efects of dopamine (DA) on several catecholaminergic cell lines involve DA oxidation products like reactive oxygen species (ROS) and toxic quinones and have implications in the pathogenesis of sporadic Parkinson’s disease (PD). However, many molecular details are yet to be elucidated, and the possible nonoxidative mechanism of dopamine cytotoxicity has not been studied in great detail. Results. Cultured SH-SY5Y cells treated with DA (up to 400 M) or lactacystin (5 M) or DA (400 M) plus N-acetylcysteine (NAC, 2.5 mM) for 24 h are processed accordingly to observe the cell viability, mitochondrial dysfunctions, oxidative stress parameters, proteasomal activity, expression of alpha-synuclein gene, and intracellular accumulation of the protein. DA causes mitochondrial dysfunction and extensive loss of cell viability partially inhibited by NAC, potent inhibition of proteasomal activity marginally prevented by NAC, and overexpression with accumulation of intracellular alpha-synuclein partially preventable by NAC. Under similar conditions of incubation, NAC completely prevents enhanced production of ROS and increased formation of quinoprotein adducts in DA-treated SH-SY5Y cells. Separately, proteasomal inhibitor lactacystin causes accumulation of alpha-synuclein as well as mitochondrial dysfunction and cell death. Conclusions. DA cytotoxicity includes both oxidative and nonoxidative modes and may involve overexpression and accumulation of alpha-synuclein as well as proteasomal inhibition. 1. Introduction Parkinson’s disease (PD), which is a progressive neurodegen- erative disorder afecting mainly the elderly people, appears in two major forms, familial and sporadic, and the latter variety accounts for nearly 90–95% of PD subjects. he pathological hallmark of PD is the degeneration of dopamin- ergic neurons of substantia nigra that project into striatum [1]. he underlying mechanisms of dopaminergic neuronal death in sporadic PD are still uncertain, but mitochondrial dysfunctions, oxidative stress, proteolytic impairment with abnormal accumulation of proteins like alpha-synuclein, and inlammatory reactions are key elements in this complex pathogenesis [1–3]. Several animal and cell-based exper- imental models have been widely used to elucidate the mechanism of dopaminergic neuronal death in sporadic Hindawi Publishing Corporation Parkinson’s Disease Volume 2014, Article ID 878935, 12 pages http://dx.doi.org/10.1155/2014/878935