Document Detail

Overexpression of DYRK1A inhibits choline acetyltransferase induction by oleic acid in cellular models of Down syndrome.
MedLine Citation:
PMID:  23124096     Owner:  NLM     Status:  MEDLINE    
Histological brain studies of individuals with DS have revealed an aberrant formation of the cerebral cortex. Previous work from our laboratory has shown that oleic acid acts as a neurotrophic factor and induces neuronal differentiation. In order to characterize the effects of oleic acid in a cellular model of DS, immortalized cell lines derived from the cortex of trisomy Ts16 (CTb) and normal mice (CNh) were incubated in the absence or presence of oleic acid. Oleic acid increased choline acetyltransferase expression (ChAT), a marker of cholinergic differentiation in CNh cells. However, in trisomic cells (CTb line) oleic acid failed to increase ChAT expression. These results suggest that the overdose of specific genes in trisomic lines delays differentiation in the presence of oleic acid by inhibiting acetylcholine production mediated by ChAT. The dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase. It has been proposed that DYRK1A plays a prominent role in several biological functions, leading to mental retardation in DS patients. Here we explored the potential role of DYRK1A in the modulation of ChAT expression in trisomic cells and in the signaling pathways of oleic acid. Down-regulation of DYRK1A by siRNA in trisomic CTb cells rescued ChAT expression up to levels similar to those of normal cells in the presence of oleic acid. In agreement with these results, oleic acid was unable to increase ChAT expression in neuronal cultures of transgenic mice overexpressing DYRK1A. In summary, our results highlight the role played by DYRK1A in brain development through the control of ChAT expression. In addition, the overexpression of DYRK1A in DS models prevented the neurotrophic effect of oleic acid, a fact that may account for mental retardation in DS patients.
Maruan Hijazi; Cristina Fillat; José M Medina; Ana Velasco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-01
Journal Detail:
Title:  Experimental neurology     Volume:  239     ISSN:  1090-2430     ISO Abbreviation:  Exp. Neurol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-01     Completed Date:  2013-02-28     Revised Date:  2013-09-27    
Medline Journal Info:
Nlm Unique ID:  0370712     Medline TA:  Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  229-34     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, (IBSAL), Spain.
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MeSH Terms
Blotting, Western
Cell Differentiation / physiology
Cell Line
Choline O-Acetyltransferase / biosynthesis*
Down Syndrome / enzymology*,  genetics*
Enzyme Induction / drug effects*,  genetics*
Mice, Transgenic
Nerve Growth Factors / pharmacology*
Oleic Acid / pharmacology*
Polymerase Chain Reaction
Protein-Serine-Threonine Kinases / biosynthesis*,  genetics*,  physiology
Protein-Tyrosine Kinases / biosynthesis*,  genetics*,  physiology
RNA, Small Interfering / genetics
Reg. No./Substance:
0/Nerve Growth Factors; 0/RNA, Small Interfering; 112-80-1/Oleic Acid; EC O-Acetyltransferase; EC 2.7.1.-/Dyrk kinase; EC Kinases; EC Kinases
Comment In:
Exp Neurol. 2013 Sep;247:110-2   [PMID:  23570900 ]

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