The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia.
Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.
Robert
Karine
K
Université Paris, Paris, France.
Santiard-Baron
Dominique
D
Chassé
Jean-Francois
JF
Paly
Evelyne
E
Aupetit
Joelle
J
Kamoun
Pierre
P
London
Jacqueline
J
Janel
Nathalie
N
D051698:Activating Transcription Factor 2; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D006710:Homocysteine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D003541:Cystathionine beta-Synthase