The cause of the neurodegenerative process in Parkinson's disease (PD) remains unclear, but evidence suggests that failure of the ubiquitin-proteasome system may play a major role in the pathogenesis of the disease. Iron is believed to be a key contributor to PD pathology by inducing aggregation of a-synuclein and by generating oxidative stress. Our present studies have shown that micro-injection of the proteasome inhibitor lactacystin into the substantia nigra (SN) of C57BL/6 mice causes significant loss of dopaminergic cells and induces intracellular inclusion body formation. We have also found that co-injection of the iron chelator desferrioxamine not only attenuates the lactacystin-induced dopamine neuron loss, but also reduces the presence of ubiquitin-positive intracellular inclusions in the SN, whereas use of iron-deficient diet has no such protective effects. These results may support that iron plays a key role in proteasome inhibitor-induced nigral pathology and that reducing iron reactivity may prevent dopaminergic neuron degeneration and reduce abnormal protein aggregation. (c) 2005 Elsevier Inc. All rights reserved.