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Analyse d'un peptide P42 protecteur de la maladie de Huntington

Abstract : Huntington’s disease (HD) is a rare genetic neurodegenerative disorder. Curative treatments are still actively sought. HD is induced by a mutation in the HTT gene inducing an abnormal expansion of the polyQ domain contained in the Huntingtin protein (Htt). Mechanisms and consequences of this mutation are now well described and allowed to identify an interaction of the Htt with the brain derived neurotrophic factor (BDNF) signaling pathway. BDNF is a neurotrophic factor, which plays important roles, through TrkB, one of its receptor, in neuronal development and plasticity. Mutant Htt (mHtt) down-regulates BDNF and TrkB transcription and transport along the axons.P42, a part of the Htt protein, is a 23aa peptide able to rescue HD pathological phenotypes, such as aggregation, axonal transport and neuronal viability.The aim of my PhD was to better understand the mechanisms of action of P42, in a purpose to optimize its therapeutic potential. To this end I developed different studies using different models.In a paper now accepted for publication in HMG, I first used a P42-based treatment on R6/2 HD mice, to analyze the effect of P42 on the BDNF/TrkB signaling pathway. To this end I analyzed pathologic phenotypes: behaviors or cell mechanisms developing in R6/2 mice and are related to the BDNF/TrkB pathway. I also measured BDNF and TrkB, mRNA or protein levels in both striatum and cortex. What I found is that P42 is acting on BDNF/TrkB pathway mainly by increasing the protein level of TrkB in the striatum.To observe the effect of P42 on vesicular transport, I rather used a Drosophila model, to perform live imaging based studies, in different transgenic conditions: with or without mHTT or P42.Also, in a way to better follow the progression of different pathological phenotypes and the effect of treatments on R6/2 mice, I benefited from a very recent and innovative tool, the HAMLET, which allows a multi-behavioral test.Finally, a bitherapy was used on R6/2 mice combining P42 and P3, a peptide raised against PolyQ mRNA that are also toxic.All those results contribute or will contribute to a better understanding of P42 mechanisms of action.
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Simon Couly. Analyse d'un peptide P42 protecteur de la maladie de Huntington. Sciences agricoles. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT022⟩. ⟨tel-01925318⟩

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