LEPEJOVA Nad'a
University : Paris XI Orsay
Jury :
- Président : P. Capy
- Rapporteurs : O. Laprevote et L. Journot
- Examinateur : F. Tronche
- Directeur de thèse : JM Elalouf
Summary
This work concerns the functional study of two genes preferentially expressed in two brain regions affected by neurodegenerative diseases: Capucin, a marker of the striatum, a structure that degenerates in Huntington's disease and Agpat4, a marker of the ventral tegmental area and the substantia nigra pars compacta, whose dopaminergic neurons are selectively affected in Parkinson's disease. Mouse lines deficient for Capucin and Agpat4 have been generated in the laboratory and during my PhD thesis I carried out their characterization.
As the striatal gene expression of Capucin is significantly reduced in mouse models of Huntington's disease, we wished to evaluate its possible role in the pathogenesis of this disease. In a collaborative work, we examined the effect of the knockout and overexpression of the Capucin gene on the vulnerability of striatal neurons to a mutant Huntingtin fragment in a mouse model of Huntington’s disease. The data show that Capucin has no significant effect on the toxicity of the mutant Huntingtin fragment in the considered model.
The Agpat4 protein has sequence homologies with acyltransferases involved in the metabolism of phosphoglycerides. I conducted expression studies using different molecular biology techniques, which showed that the Agpat4 gene is expressed in most catecholaminergic tissues. To determine the endogenous activity of Agpat4 and its physiological role in the tissues where it is expressed, I compared the metabolomes of Agpat4-deficient and wild-type mice tissues by liquid chromatography coupled with mass spectrometry. My results indicate that Agpat4 deficiency alters not only the metabolism of different lipid classes, in particular lysophosphatidylethanolamines, but also the metabolism of catecholamines.
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