Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration.
Impairment of the ubiquitin proteasome system (UPS) and iron accumulation in the substantia nigra (SN) have both been implicated in the pathogenesis of Parkinson's disease (PD). We previously reported that chemical iron chelation can protect against proteasome inhibitor lactacystin-induced dopamine (DA) neurodegeneration in vivo. Here, we tested potential neuroprotection via genetic expression of the iron chelator human ferritin heavy chain (H-ferritin). We found that overexpression of H-ferritin in DA neurons significantly reduced lactacystin-induced nigral DA neuron loss and striatal DA depletion. Overexpression of H-ferritin also attenuated elevated levels of total and ferrous iron as well as the divalent metal ion transporter 1 (DMT1) in the SN following lactacystin treatment. In addition, overexpression of H-ferritin alleviated the inhibitory effects of lactacystin on proteasome activity in the nigral tissues. These results suggest that H-ferritin exerts neuroprotection possibly by modulating iron homeostasis and restoring proteasome activity.
Zhu
Wen
W
Department of Neurology, NB 205, Baylor College of Medicine, Houston, TX 77030, USA.
Li
Xuping
X
Xie
Wenjie
W
Luo
Feifei
F
Kaur
Deepinder
D
Andersen
Julie K
JK
Jankovic
Joseph
J
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001052:Apoferritins / Q000235:genetics*; D027682:Cation Transport Proteins / Q000378:metabolism; D015913:Chelation Therapy / Q000379:methods; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019610:Cytoprotection / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D000099236:Solute Carrier Family 11, Member 2
D000111:Acetylcysteine; D001052:Apoferritins; D027682:Cation Transport Proteins; D015853:Cysteine Proteinase Inhibitors; D004298:Dopamine; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D000099236:Solute Carrier Family 11, Member 2; C067713:lactacystin