1994). This high oxidative environment promotes deposition of ubiquitin and alpha synuclein inclusion or putative Lewy bodies in the cytoplasm of DA neurons (Spillantini et al. 1997). The naturally occurring antioxidant glutathione is lower in the SN of PD (Bharath et al. 2002) Adding to the vulnerability of the SN to oxidative stress is its high density of microglia as compared to other brain areas (Kim et al. 2000). As noted above, microglia Inhibitors,research,lifescience,medical activation and release of proinflammatory cytokine promotes oxidative stress. TNF- α, INF- γ, IL-1β can all activate iNOS contributing to the formation of the highly

active ROS, nitric oxide (Hunot et al. 1996; Delgado 2003). Postmortem SN samples from PD patients show elevated numbers of microglia coexpressing iNOS as compared to controls (Hunot et al. 1996; Knott et al. 2000). Thus, activated microglia and their production of ROS is thought to be the major source of oxidative stress contributing to the death of DA neurons Inhibitors,research,lifescience,medical in PD (Jenner 1998;

Koutsilieri et al. 2002) and the accumulation of ferrous ions, decreased glutathione (Bharath et al. 2002). Indeed, iron deposition in the SN is another hallmark of PD (Hirsch et al. 1991; Sofic et al. 1991; Song et al. 2007) as is increased DNA damage due to oxidation of guanine and the formation of 8-oxo-dG (Fleming et al. 1994; Alam et al. 1997; Zhang Inhibitors,research,lifescience,medical et al. 1999; Kikuchi et al. 2002). Again, both measures of oxidative stress are present in Inhibitors,research,lifescience,medical this model of PD. As noted above, the susceptibility of DA to oxidative modification can contribute to the toxic environment of SN. The metabolism and auto-oxidation of DA in the cytosol of SN neurons is safeguarded, in part, by the sequestration of DA in synaptic vesicles. This function is carried out by VMAT2 (for review see Taylor et al. 2011). The activity of VMAT2, in addition, to regulating synaptic neurotransmission, confers a level of protection to cellular damage in DA nerve terminals. Loss of VMAT2 function might Inhibitors,research,lifescience,medical be expected to be one risk factor contributing to the pathophysiology of PD. MAPK inhibitor levels of

VMAT2 are reduced in the striatum of PD brain samples (Miller et al. 1999) and in positron emission tomography (PET) studies on PD patients (Kilbourn et al. 1993; Frey et al. 1996; Lee et al. 2000; Martin et al. 2008; Okamura et al. 2010). VMAT2 levels correlate with the severity of Parkinsonism; hence, PET imaging of VMAT2 offers a sensitive in vivo method for detecting Tryptophan synthase the early loss of DA nerve terminals in the striatum and may serve as a biomarker of presymptomatic PD. The significant decrease in VMAT2 immunostaining in this rotenone microsphere model PD supports this notion The most intriguing aspect of this model of PD was the modest but significant increase in DAT, the dopamine transporter. DAT is widely used as a molecular biomarker to assess the integrity of presynaptic DA nerve terminals in the caudate/putamen (for review see Brooks 2010).