DYRK1A, a novel determinant of the methionine-homocysteine cycle in different mouse models overexpressing this Down-syndrome-associated kinase.
BACKGROUND
Hyperhomocysteinemia, characterized by increased plasma homocysteine level, is associated with an increased risk of atherosclerosis. On the contrary, patients with Down syndrome appear to be protected from the development of atherosclerosis. We previously found a deleterious effect of hyperhomocysteinemia on expression of DYRK1A, a Down-syndrome-associated kinase. As increased expression of DYRK1A and low plasma homocysteine level have been associated with Down syndrome, we aimed to analyze the effect of its over-expression on homocysteine metabolism in mice.


RESULTS
Effects of DYRK1A over-expression were examined by biochemical analysis of methionine metabolites, real-time quantitative reverse-transcription polymerase chain reaction, and enzyme activities. We found that over-expression of Dyrk1a increased the hepatic NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities, concomitant with decreased level of plasma homocysteine in three mice models overexpressing Dyrk1a. Moreover, these effects were abolished by treatment with harmine, the most potent and specific inhibitor of Dyrk1a. The increased NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities were also found in lymphoblastoid cell lines from patients with Down syndrome.


CONCLUSIONS
Our results might give clues to understand the protective effect of Down syndrome against vascular defect through a decrease of homocysteine level by DYRK1A over-expression. They reveal a link between the Dyrk1a signaling pathway and the homocysteine cycle.
Noll
Christophe
C
University Paris Diderot-CNRS EAC 4413, Unit of Functional and Adaptive Biology, Paris, France.
Planque
Chris
C
Ripoll
Clémentine
C
Guedj
Fayçal
F
Diez
Anna
A
Ducros
Véronique
V
Belin
Nicole
N
Duchon
Arnaud
A
Paul
Jean-Louis
JL
Badel
Anne
A
de Freminville
Bénédicte
B
Grattau
Yann
Y
Bléhaut
Henri
H
Herault
Yann
Y
Janel
Nathalie
N
Delabar
Jean-Maurice
JM
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006247:Harmine / Q000494:pharmacology; D006710:Homocysteine / Q000097:blood* / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors; D000097603:Dyrk Kinases
D006247:Harmine; D006710:Homocysteine; D008715:Methionine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases