Role of iron in UPS impairment model of Parkinson's disease

Iron homeostasis requires the regulation of iron influx, iron efflux and iron storage, which are all essential to the execution of the multiple functions of the central nervous system. Abnormal accumulation of iron in the brain has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD) and neurodegeneration with brain iron accumulation (NBIA). Although the cause of the neurodegenerative process in PD remains unclear, recent evidence suggests that failure of the ubiquitin-proteasome system (UPS) may play an important role in the pathogenesis of this disease. Our studies have shown that injection of the proteasome inhibitor lactacystin in the substantia nigra (SN) of rodents causes significant loss of dopamine (DA) neurons and induces intracellular inclusion body formation, which is accompanied by excessive iron accumulation in the midbrain. In the in vitro model, lactacystin causes a marked increase in labile iron, reactive oxygen species, alteration of iron regulatory protein (IRP)/iron response element expression levels, and an increase in the aggregation of ubiquitin-conjugated proteins prior to cell injury and death. Furthermore, we have demonstrated that synthetic iron chelators and a genetic iron chelator are neuroprotective against proteasome inhibitor-induced DA neuron degeneration, suggesting that iron chelation might be a promising therapeutic target for PD.