Toxic effects of the oxidized products of the neurotransmitter dopamine on mitochondria and their implications in Parkinson's disease

Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder clinically characterized by motor symptoms such as tremor at rest, rigidity, slowness of movement (bradykinesia), and postural instability. One pathological hallmark of the disease is the progressive and striking loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It is unclear why SNpc neurons die during PD. However, several biochemical hallmarks of the disease exist, and likely reveal clues to the underlying etiology of PD. Mitochondrial dysfunctions, at the level of complex I of the electronic transport chain (ETC), have been reported in the SNpc of PD patients. It has been hypothesized that the reason dopaminergic neurons of SNpc are vulnerable in PD is due to the toxic properties of the DA itself. DA is a highly reactive molecule, normally stored in synaptic vesicles. Increasing cytosolic dopamine in neurons and its oxidized metabolites has many deleterious effects, including increases in oxidative stress, mitochondrial dysfunction.The overall aim of the research that this dissertation comprises is to identify the mechanism that contributes to the selective degeneration of dopaminergic neurons in PD. The research described herein utilizes in vitro and cellular model approaches to test the hypothesis that the oxidized products of the neurotransmitter DA (DAQs) induce toxic effects on mitochondria. If this hypothesis is correct any pathological event that impairs DA synthesis, storage or metabolism, leading to the cytoplasmic accumulation of DA can increase the presence of oxidized products of DA and their toxic effects in the cell with mitochondria as one of the target. Mitochondrial dysfunctions derived from exposure to DA-oxidized products can account for the specific vulnerability of dopaminergic neurons and their degeneration in PD.