Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration.
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 alpha-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.
Zhang
Xiong
X
Department of Neurology, The 2nd Affiliated Hospital to Wenzhou Medical College, China.
Xie
Wenjie
W
Qu
Shen
S
Pan
Tianhong
T
Wang
Xiaotong
X
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D003676:Deferoxamine / Q000008:administration & dosage*; D007502:Iron Chelating Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D061988:Proteasome Inhibitors; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome; D025801:Ubiquitin / Q000378:metabolism
D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C067713:lactacystin; D003676:Deferoxamine; D000111:Acetylcysteine