Although much research into the etiology of PD has taken place, this has very largely focused on the role of mutant proteins in familial PD. Fourteen or more genetic loci have been identified and the pathophysiological action of mutant proteins encoded by genes in these loci are being elucidated. Nevertheless, the contribution of genetic mutation to the overall burden of PD is very small. The most optimistic estimates that are around 5–10% of all PD cases are due to such mutations. Of the remaining 90–95%, arguments have been made to show that environmental factors such as pesticide exposure are involved. This may be the case in a certain number of Inhibitors,research,lifescience,medical instances. Nonetheless, whether
a combination of a genetic susceptibility and toxin exposure accounts for the majority of cases of sporadic PD remains unclear. If these two factors are not the cause, it would be logical Inhibitors,research,lifescience,medical to look at the physiology of the brain itself. The hypothesis put forward by Surmeier and colleagues uses this as a basis (Guzman et al. 2009, 2010). They have pointed out that dopaminergic ABT-888 mouse neurons of the substantia nigra have a relatively rare Inhibitors,research,lifescience,medical mechanism of autonomous pacemaking. During pacemaking in these neurons, calcium entry occurs via L-type Ca2+ channels with a Cav1.3 pore-forming subunit. They proposed
that the relatively open nature of these channels allows greater calcium entry, which in turn incurs a high metabolic cost in terms of ATP Inhibitors,research,lifescience,medical to maintain tight control of intracellular calcium by the endoplasmic reticulum and the mitochondria. The high ATP requirement, which has to be met by mitochondrial synthesis, results in greater Inhibitors,research,lifescience,medical ROS production that ultimately overwhelms neuronal antioxidant defenses and leads to cell death. Whether the complete
scenario envisaged by Surmeier et al. (2011) is correct awaits further substantiation. Nonetheless, there is long-established evidence for the role of calcium in the control of mitochondrial substrate oxidation (Hansford and Zorov 1998) and in neuronal cell death (Stout et al. 1998). This evidence has led to the possible involvement of UCPs, and UCP4 in particular. Chan et al. (2006), using PC-12 cell clones which either express UCP4 or not, have shown that UCP4 is a potent influence on store-operated calcium entry and Tolmetin on mitochondrial sequestration of calcium (Chan et al. 2006). They proposed that prevention of calcium overload by UCP4 inhibition of store-operated calcium channels, with consequent reduction in oxidative stress, reduces the likelihood of calcium-primed cell death. Furthermore, in a DJ-1 knockout mouse model, the expression of both UCP4 and UCP5 was downregulated and DJ-1 modulated the magnitude of the response of these two UCPs to oxidative stress (Guzman et al. 2010).