Fig. 1

Central role of chronic oxidative stress in mediating PD progression. Mitochondria depolarization, ER stress, α-synuclein accumulation and increased level of cytosolic DA are known PD phenotypes that potentially contribute to cellular oxidative stress, alone or by interacting with each other. ER regulates cytosolic calcium and thus prevents excess uptake by MCU that otherwise can stimulate ETC and ROS production in mitochondria, an essential function in neurons with intense depolarization. α-synuclein accumulation can contribute to ER stress by binding to ER chaperones and disturbing vesicle trafficking between ER and Golgi. While UPR activation also stimulate α-synuclein aggregation by unclear mechanism. Utilization of DA risks midbrain DA neurons to oxidative damage by DA metabolism. Additionally, DA has been shown to trigger α-synuclein oligomer formation and mitochondria depolarization. Altogether, these phenotypes produce oxidative environment that further amplifies the damage. Mutations that disturb the function of LRRK2, DJ-1, Parkin and PINK1 have been linked to familial cases of PD. Parkin is an E3 ubiquitin ligase and dysfunctionality of this protein results in accumulation of its substrates. Together with PINK1, Parkin is also responsible to clear up damaged mitochondria. One of DJ-1 putative role as sensor of oxidative stress may be necessary in cell protection. Single mutation in LRRK2 resulted in increased susceptibility towards oxidative stressor, even though the mechanism is less understood. Pesticide rotenone, iron and manganese also cause cellular oxidative stress by triggering mitochondria depolarization, α-synuclein oligomerization together with ROS production and UPR activation, respectively. Long term exposure of those substances has been linked with higher risk of developing sporadic PD