Document Detail

Proteasome inhibition increases DNA and RNA oxidation in astrocyte and neuron cultures.
MedLine Citation:
PMID:  15569264     Owner:  NLM     Status:  MEDLINE    
Increased levels of nucleic acid oxidation have been described as part of normal brain aging and have been demonstrated to occur in multiple neurological disorders. The basis for increased nucleic acid oxidation in each of these conditions is presently unknown. Proteasome inhibition occurs in a host of neurodegenerative conditions and likely contributes to increased levels of oxidative damage and neurotoxicity. In the present study we demonstrate for the first time the ability of proteasome inhibition to increase the level of nucleic acid oxidation in primary neuron and astrocyte cultures. Administration of proteasome inhibitors (MG262, MG115) at concentrations that do not induce neuron death in the first 24 h of treatment, dramatically increase the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8OHG) immunoreactivity in both cell types. Neurons underwent larger increases in nucleic acid oxidation compared to astrocyte cultures. While both DNA and RNA oxidation were observed following proteasome inhibition, RNA appeared to undergo a greater degree of oxidation than DNA. Both 18S and 28S ribosomal RNA were dramatically decreased following proteasome inhibition. Interestingly, an accumulation of unprocessed and/or cross-linked RNA species was observed following proteasome inhibition. Taken together, these data indicate the ability of proteasome inhibition to increase the levels of nucleic acid oxidation in both neurons and astrocytes, and suggest that proteasome inhibition may have deleterious effects on transcription and translation in both neurons and glia.
Qunxing Ding; Edgardo Dimayuga; William R Markesbery; Jeffrey N Keller
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  91     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-30     Completed Date:  2005-02-10     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1211-8     Citation Subset:  IM    
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
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MeSH Terms
Astrocytes / drug effects*,  metabolism
Blotting, Western / methods
Boronic Acids / pharmacology
Brain / cytology
Cells, Cultured
DNA / metabolism*
Deoxyadenosines / metabolism
Embryo, Mammalian
Guanosine / analogs & derivatives*,  metabolism
Immunohistochemistry / methods
Leupeptins / pharmacology
Neurons / drug effects*,  metabolism
Oxidation-Reduction / drug effects
Protease Inhibitors / pharmacology*
RNA / metabolism*
RNA, Ribosomal, 16S / metabolism
RNA, Ribosomal, 28S / metabolism
Time Factors
Grant Support
5P01-AG005119/AG/NIA NIH HHS; 5P50-AG05114/AG/NIA NIH HHS; AG018347/AG/NIA NIH HHS
Reg. No./Substance:
0/8-hydroxy-2'-deoxyadenosine; 0/Boronic Acids; 0/Deoxyadenosines; 0/Leupeptins; 0/MG 262; 0/Protease Inhibitors; 0/RNA, Ribosomal, 16S; 0/RNA, Ribosomal, 28S; 0/carbobenzoxy-leucyl-leucyl-norvalinal; 118-00-3/Guanosine; 3868-31-3/8-hydroxyguanosine; 63231-63-0/RNA; 9007-49-2/DNA

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

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