Document Detail


Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models.
MedLine Citation:
PMID:  16870259     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Impairment in ubiquitin-proteasome system (UPS) has recently been implicated in Parkinson's disease, as demonstrated by reduced proteasomal activities, protein aggregation and mutation of several genes associated with UPS. However, experimental studies with proteasome inhibitors failed to yield consensus regarding the effect of proteasome inhibition on dopaminergic degeneration. In this study, we systematically examined the effect of the proteasome inhibitor MG-132 on dopaminergic degeneration in cell culture and animal models of Parkinson's disease. Exposure of immortalized dopaminergic neuronal cells (N27) to low doses of MG-132 (2-10 microM) resulted in dose- and time-dependent cytotoxicity. Further, exposure to MG-132 (5 microM) for 10 min led to dramatic reduction of proteasomal activity (>70%) accompanied by a rapid accumulation of ubiquitinated proteins in these cells. MG-132 treatment also induced increases in caspase-3 activity in a time-dependent manner, with significant activation occurring between 90 and 150 min. We also noted a 12-fold increase in DNA fragmentation in MG-132 treated N27 cells. Similarly, primary mesencephalic neurons exposed to 5 microM MG-132 also induced >60% loss of TH positive neurons but only a minimal loss of non-dopaminergic cells. Stereotaxic injection of MG-132 (0.4 microg in 4 microl) into the substantia nigra compacta (SNc) in C57 black mice resulted in significant depletion of ipisilateral striatal dopamine and DOPAC content as compared to the vehicle-injected contralateral control sides. Also, we observed a significant decrease in the number of TH positive neurons in the substantia nigra of MG-132-injected compared to the vehicle-injected sites. Collectively, these results demonstrate that the proteasomal inhibitor MG-132 induces dopamine depletion and nigral dopaminergic degeneration in both cell culture and animal models, and suggest that proteasomal dysfunction may promote nigral dopaminergic degeneration in Parkinson's disease.
Authors:
Faneng Sun; Vellareddy Anantharam; Danhui Zhang; Calivarathan Latchoumycandane; Arthi Kanthasamy; Anumantha G Kanthasamy
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2006-06-29
Journal Detail:
Title:  Neurotoxicology     Volume:  27     ISSN:  0161-813X     ISO Abbreviation:  Neurotoxicology     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-08-21     Completed Date:  2006-10-31     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7905589     Medline TA:  Neurotoxicology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  807-15     Citation Subset:  IM    
Affiliation:
Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, 2062 Veterinary Medicine Building, Ames, IA 50011-1250, USA.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Caspase 3
Caspases / metabolism
Cell Death / drug effects
Cells, Cultured
Cysteine Proteinase Inhibitors / toxicity*
DNA Fragmentation / drug effects
Disease Models, Animal
Dopamine / metabolism*
Dose-Response Relationship, Drug
Embryo, Mammalian
Immunohistochemistry / methods
Leupeptins / toxicity*
Mesencephalon / cytology
Mice
Mice, Inbred C57BL
Nerve Degeneration / chemically induced*,  metabolism
Neurons / drug effects*,  metabolism
Neurotransmitter Agents / metabolism
Proteasome Endopeptidase Complex / antagonists & inhibitors
Rats
Tyrosine 3-Monooxygenase / metabolism
Grant Support
ID/Acronym/Agency:
ES 10586/ES/NIEHS NIH HHS; NS 45133/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Cysteine Proteinase Inhibitors; 0/Leupeptins; 0/Neurotransmitter Agents; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; EC 1.14.16.2/Tyrosine 3-Monooxygenase; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 3.4.25.1/Proteasome Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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