Parkinson’s disease is a widespread neurodegenerative disorder that affect 2% of the population above the age of 60. The hallmark of the pathology is the preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain, and the presence of proteinaceous inclusions called Lewy bodies in the surviving neurons (Braak 2004). In 10% of the cases, the disease is linked to mutation on several genes, among them α-synuclein, DJ-1, PARKIN, PINK1 and LRRK2, but in the vast majority of the cases the aetiology is still unknown (sporadic PD) (Gwinn-Hardy 2002). Post mortem studies and in vitro and in vivo PD model have revealed a possible interconnection between genetic and sporadic PD, which involves both mitochondrial dysfunction and oxidative stress as central players in the pathogenesis of the disease (Gilgun-Sherki Y. et al. 2001, Mythri R. B. et al. 2011). Oxidative stress is a condition characterized by the inability of the cellular antioxidant defences to cope with the production of reactive oxygen species (ROS). This condition of unbalance between the production and the clearance of ROS causes irreversible damage to cellular components such as lipids, proteins and DNA, leading eventually to cell death (Lotharius et al. 2002). Among the enzymes implicated in the detoxification of ROS, are superoxide dismutases (SODs) that catalyze the dismutation of superoxide anion into molecular oxygen and hydrogen peroxide (Fridovich 1995). Since oxidative stress does not explain alone the selectivity death of dopaminergic neurons, the main working hypothesis is that dopamine itself could have a central role. Under physiological conditions, dopamine is synthesized in the cytosol and stored in synaptic vesicles by the action of Vesicular Monoamine Transporter (VMAT2) where it is stabilized by the low pH (Erickson, J. D 1992). If the amount of cytosolic DA exceeds the physiological concentration, DA is metabolized to the non-toxic metabolite 3,4-dihydroxyphenylacetic acid and hydrogen peroxide by the action of monoamine oxidase (MAO) and aldehyde dehydrogenase, or sequestered into lysosomes where it can auto-oxidize to form neuromelanin (NM). If not buffered by these pathways, cytosolic DA can be oxidized to DA-quinone (DAQs) (spontaneously or enzymatically), (Sulzer, D., 2000, Elsworth, J. D. 1997), a reaction that also leads to the formation of ROS. On these premise, we evaluated two line of research using a cellular model for PD (SH SY5Y cell line): one concerning about the effect of dopamine and its oxidized forms on cellular viability, the second one on the potential role of superoxide dismutases (1 and 2) over expression. From the use of different techniques we started to evaluate which kind of cell death pathway was activated by dopamine and DAQs. Looking for the presence of nuclear fragmentation, that is one of the later stages of apoptosis, we determined that both dopamine and DAQs induce cell death via apoptosis but the dopamine toxicity depends on its internalization by the action of the dopamine transporter (DAT), since the pre-treatment of cells with GBR 12909 (a DAT inhibitor) had a rescue effect. To confirm the apoptotic pathway we also evaluated another hallmark of apoptosis (one of the former stages of the apoptotic cascade): phosphatidil-serine externalization (PS) using ANNEXIN-V-FLUOS; a specific probe for PS. Using flow cytometry we confirm that both dopamine and DAQs induce cell death via apoptosis. Next we wanted to evaluate if dopamine and DAQs exert their toxicity from extracellular environment or they are required to enter in the cells. Treating cells with GBR12909, we demonstrate that dopamine needs to enter cells to exert its toxicity (since the treatment with the DAT inhibitor rescues cells from DA toxicity) while DAQs toxicity was not affected by this treatment leading to cell death. Since oxidative stress is one of the mechanisms that have been implicated in the pathogenesis of PD, and the chemistry of dopamine (auto-oxidation and enzyme-mediated oxidation) leads to the production of ROS, we evaluate the production of mitochondrial superoxide anion using a specific probe. The data demonstrate that only the auto oxidation of dopamine leads to the production of superoxide anion and dopamine is required to enter cell to exert its effect. To dissect more in depth the toxicity mechanism of both dopamine and DAQs, and since only cytosolic dopamine led to the production of mitochondrial superoxide anion, we asked if this two different oxidation processes activated different cell death pathways (the major are the mitochondrial one and the one mediated by death receptor) or not. From preliminary data we observed a marked difference in the activation of caspase 3 and the subsequent cleavage and inactivation of Poly (ADP) ribose polymerase (PARP) due to DAQs treatment convincing us to proceed in the investigation of the possible differences between this different oxidation processes. The second part of the work was focused on the role for superoxide dismutases 1 and 2 against dopamine and DAQs cytotoxicity since previous data demonstrated a role in superoxide anion production and induction of cell death in the case of cytosolic dopamine. Over expression of both SOD1 and SOD2 revealed a protective effect against dopamine cytotoxity, while they were not able to counteract DAQs-induced cell death. In the present work the main working hypothesis was that oxidative stress induced by dopamine and its oxidized forms accumulation could have a central role in the specific dopaminergic cell loss in Parkinson’s disease. The data obtained so far seems to highlights that dopamine and DAQs activates different apoptotic pathway that are superoxide anion-dependent for DA and superoxide anion-independent for DAQs. Since oxidative stress is considered one of the mechanism that interconnect genetic form and sporadic forms of the pathology and dopamine, in its oxidative chemistry, leads to the production of ROS, understanding which cell death pathways are activated and to which extent, is crucial to develop a therapy to counteract the start and the progression of the pathology. Data from the over expression of SODs demonstrate that compounds that counteract the production of superoxide anion (like SOD-mimetics that are currently used for other diseases) could have a protective role against the oxidative stress and the subsequent cell death condition induced by dopamine. Also compounds that block the activation of the apoptotic cascade induced by dopamine and DAQs could rescue cells from dying in this neurodegenerative disease