Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder and increasingly a major burden in an aging population. Although its pathogenesis is unknown, there is evidence to implicate common pathogenic processes towards eventual cell death in PD. These processes include mitochondrial dysfunction, oxidative stress, neuroinflammation, excitotoxicity, and ubiquitin proteasome dysfunction [1-4].There is considerable evidence to link mitochondrial dysfunction and PD. Mitochondrial Complex I activity is reduced in substantia nigra in PD [5]. Inhibition of Complex I activity using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone (both toxins used in experimental parkinsonian models) produce nigrostriatal dopaminergic degeneration in animal models [6,7]. Cybrid cell lines with normal nuclear genome but with mitochondrial DNA from PD patients have reduced Complex I activity and mitochondrial energy-dependent activities [8], have abnormal mitochondrial morphology [9], and are more susceptible to MPTP-induced toxicity. The process of aging involves the mitochondria [10]. Furthermore, dopamine metabolism and mitochondrial dysfunction generate oxidative stress. High basal levels of oxidative stress in substantia nigra are found in normal brain, and are increased in PD. Furthermore, antioxidant activity, such as glutathione (GSH), is reduced in substantia nigra of PD patients [11,12]. Based on the hypothesis that various genetic and environmental etiological factors converge on these common pathogenic processes in PD, targeting proteins which modulate mitochondria bioenergetics appears to be a logical approach in preserving neurons against mitochondrial dysfunction in PD.Mitochondria are rod-shaped cellular organelles, which range in size from between 1 and 10 microns in length. They provide cellular energy by converting oxygen and nutrients into adenosine triphosphate (ATP) via oxidative phosphorylation. Human cells have hundreds to thousands of mitochondria