Zn2+ mediates ischemia-induced impairment of the ubiquitin-proteasome system in the rat hippocampus.
Abstract Deposition of ubiquitinated protein aggregates is a hallmark of neurodegeneration in both acute neural injuries, such as stroke, and chronic conditions, such as Parkinson's disease, but the underlying mechanisms are poorly understood. In the present study, we examined the role of Zn2+ in ischemia-induced impairment of the ubiquitin-proteasome system in the CA1 region of rat hippocampus after transient global ischemia. We found that scavenging endogenous Zn2+ reduced ischemia-induced ubiquitin conjugation and free ubiquitin depletion. Furthermore, exposure to zinc chloride increased ubiquitination and inhibited proteasomal enzyme activity in cultured hippocampal neurons in a concentration- and time-dependent manner. Further studies of the underlying mechanisms showed that Zn(2+)-induced ubiquitination required p38 activation. These findings indicate that alterations in Zn2+ homeostasis impair the protein degradation pathway.
Institute of Neuroscience State, Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Min
M
Chen
Qian
Q
Chen
Xue-Wen
XW
Cheng
Ting-Jia
TJ
Lu
Han-Xing
HX
Liu
Jie-Min
JM
Jia
Chi
C
Zhang
Li
L
Xu
Zhi-Qi
ZQ
Xiong
D000199:Actins / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003374:Coumarins / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection / Q000379:methods; D025801:Ubiquitin / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D000199:Actins; D002614:Chelating Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007093:Imidazoles; D007976:Leupeptins; D008869:Microtubule-Associated Proteins; D009842:Oligopeptides; D011743:Pyrimidines; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C046582:succinyl-leucyl-leucyl-valyl-tyrosyl-methylcoumarinamide; D004492:Edetic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C406525:SB 239063; D015032:Zinc; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde