Document Detail


Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans.
MedLine Citation:
PMID:  18160657     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the CNS after injury and participate in the inhibition of axon regeneration mainly through their glycosaminoglycan (GAG) side chains. In the present study, we have identified a new way to alleviate the inhibition of axonal regeneration by CSPG GAGs. We have successfully decreased the amount of CSPG GAG produced by astrocytes by targeting chondroitin polymerizing factor (ChPF), a key enzyme in the CSPG biosynthetic pathway. Using short interfering RNA (siRNA), we reduced ChPF mRNA levels by 70% in both the Neu7 astrocyte cell line and primary rat astrocytes. This reduction leads to a decrease in ChPF protein levels and a reduced amount of CSPG GAG chains in the conditioned media (CM) of these cells. Secretion of neurocan by primary astrocytes and NG2 core protein by Neu7 cells transfected with ChPF siRNA is not decreased, suggesting that inhibiting GAG chain synthesis does not affect core protein trafficking from these cells. CM from siRNA-treated Neu7 cells is a less repulsive substrate for axons than CM from control cells. In addition, axonal outgrowth from cerebellar granule neurons is increased on or in CM from ChPF siRNA-treated Neu7 cells. These data indicate that targeting the biosynthesis of CSPG GAG is a potentially new therapeutic avenue for decreasing CSPG GAG produced by astrocytes after CNS injury.
Authors:
Tracy L Laabs; Hang Wang; Yasuhiro Katagiri; Thomas McCann; James W Fawcett; Herbert M Geller
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  27     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-27     Completed Date:  2008-02-05     Revised Date:  2010-12-03    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14494-501     Citation Subset:  IM    
Affiliation:
Developmental Neurobiology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Astrocytes / chemistry*,  drug effects,  metabolism*
Axons / drug effects,  physiology
Brain / cytology
Cells, Cultured
Chondroitin Sulfate Proteoglycans / pharmacology*
Culture Media, Conditioned / pharmacology
Enzyme-Linked Immunosorbent Assay / methods
Gene Expression Regulation / drug effects,  physiology
Glycosaminoglycans / metabolism*
Membrane Proteins / metabolism*
Neurites / drug effects,  metabolism
RNA, Small Interfering / pharmacology
Rats
Rats, Sprague-Dawley
Time Factors
Transfection / methods
Grant Support
ID/Acronym/Agency:
070467//Wellcome Trust
Chemical
Reg. No./Substance:
0/Chondroitin Sulfate Proteoglycans; 0/Culture Media, Conditioned; 0/Glycosaminoglycans; 0/Membrane Proteins; 0/RNA, Small Interfering
Comments/Corrections
Comment In:
J Neurosci. 2008 Mar 12;28(11):2688-9   [PMID:  18337397 ]

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


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