Document Detail


Proteasome inhibitor lactacystin induces cholinergic degeneration.
MedLine Citation:
PMID:  20437934     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Ubiquitin proteasome system dysfunction is believed to play an important role in the development of Parkinson's disease (PD), and almost all studies till now have mainly focused on the susceptibility of dopaminergic neurons to proteasome inhibition. However, in fact, there are many other types of neurons such as cholinergic ones involved in PD. In our present study, we attempt to figure out what effect the failure of ubiquitin proteasome function would execute on cholinergic cells in culture. METHODS: We treated cholinergic cells in culture with various doses of lactacystin. Then MTT assay was used to evaluate the cellular viability and the AnnexinV-PI method was used to detect apoptosis. Both cellular soluble and insoluble polyubiquitinated proteins were detected by western blot. Furthermore, the mitochondrial membrane potential was analyzed using JC-1 and the intracellular production of reactive oxygen species (ROS) was determined using the fluorescent probe CM-H2DCFDA. RESULTS: We found that low doses of lactacystin were enough to induce significant apoptotic cell death, disturb the mitochondrial membrane potential, and cause oxidative stress. We also found that the amounts of polyubiquitinated proteins dramatically increased with high doses, although the loss of cells did not increase accordingly. CONCLUSIONS: Our results suggest that cholinergic cells are sensitive to ubiquitin proteasome system dysfunction, which exerts its toxic effect by causing mitochondrial dysfunction and subsequent oxidative stress, not through polyubiquitinated proteins accumulation.
Authors:
Hai-Yan Zhou; Yu-Yan Tan; Zhi-Quan Wang; Gang Wang; Guo-Qiang Lu; Sheng-Di Chen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques     Volume:  37     ISSN:  0317-1671     ISO Abbreviation:  Can J Neurol Sci     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-05-04     Completed Date:  2010-05-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0415227     Medline TA:  Can J Neurol Sci     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  229-34     Citation Subset:  IM    
Affiliation:
Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
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MeSH Terms
Descriptor/Qualifier:
Acetylcholine / metabolism*
Acetylcysteine / analogs & derivatives*,  pharmacology
Animals
Annexin A5 / metabolism
Apoptosis / drug effects*
Cell Line, Transformed
Cell Survival / drug effects
Cysteine Proteinase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Flow Cytometry / methods
Gene Expression Regulation / drug effects
Membrane Potential, Mitochondrial / drug effects
Mice
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism
Ubiquitin C / metabolism
Chemical
Reg. No./Substance:
0/Annexin A5; 0/Cysteine Proteinase Inhibitors; 0/Reactive Oxygen Species; 0/Ubiquitin C; 133343-34-7/lactacystin; 51-84-3/Acetylcholine; 616-91-1/Acetylcysteine

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


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