Abstract
Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in Parkinson's disease (PD). In recent years, environmental toxins are employed to increase oxidative stress mediated neuropathology and sporadic PD. Disruption of iron homeostasis has been implicated in PD patients for many years, but the functional role of iron in sporadic PD pathogenesis is still not well clarified in vivo. To address this question, we set out to investigate the effect of iron on a Drosophila rotenone model of sporadic PD. Iron homeostasis is maintained by many transporters. We found that inhibition of transferrin1 (Tsf1) expression in the central nervous system (CNS) results in reduced iron levels in brains and significantly ameliorates the neurodegenerative phenotypes of rotenone exposure Drosophila; moreover, the rotenone induced reactive oxygen species (ROS) levels in the brain, the damaged complex I activity and the decreased ATP generation were dramatically rescued by Tsf1 knockdown. Further study indicated that all the rescue effects of Tsf1 knockdown on sporadic PD could be inhibited by malvolio (Mvl) overexpression, an iron transporter responsible for iron uptake. These results imply that Tsf1 knockdown in the CNS could attenuate rotenone toxicity by decreasing the ROS levels in brains through reducing iron levels, and manipulation of iron transporters in brains may provide a novel therapeutic strategy for sporadic PD.
