Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

Figure 1

The mitochondrial cascade hypothesis for PD states that the inherited electron transport chain gene combinations determine basal ETC efficiency and ROS production. This defines the rate at which acquired mtDNA alterations occur determining when mitochondrial impairment reaches a threshold that activates the pathologic characteristics of PD. Mitochondrial impairment in PD is characterized by a complex I defect, which leads to ATP depletion and NAD⁺/NADH ratio imbalance promoting microtubule disruption. Moreover, mitochondrial membrane potential is lost and calcium homeostasis is deregulated, which leads to calpains activation. In addition, the levels of mitochondrial ROS are significantly increased triggering oxidative stress. These all prompt alpha-syn oligomerization either by interaction with free tubulin, calpains or by oxidation. The end result is alpha-syn oligomerization and accumulation of alpha-syn oligomers as well as of disrupted organelles culminating in neurodegeneration.