Tesis Doctoral C/ Eduardo Primo Yúfera, 3 (junto Oceanográfico) · 46012 VALENCIA (Spain) · Tel: +34 96 328 96 80 - Fax: +34 96 328 97 01 / www.cipf.es / CIF G-46/923421 New models and molecular mechanisms in Charcot-Marie-Tooth disease caused by GDAP1 mutations Thesis Direction: Dr. Máximo Ibo Galindo Orozco 10/03/2017 – 12:30 h Salón de Actos CIPF Abstract: One of the genes involved in Charcot Marie Tooth disease, an inherited peripheral neuropathy, is GDAP1, which encodes a protein anchored to the mitochondrial outer membrane. The Drosophila CG4623 gene is the true ortholog of human GDAP1, and we have renamed it Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show changes in mitochondrial size, morphology and distribution; and neuronal and muscular degeneration. The study of different molecular aspects indicates that changes in oxidative stress happen only in the long term and are not a primary cause. A metabolomic study using nuclear magnetic resonance (NMR), reveals that up- and down-regulation of Gdap1 result in accumulation of carbohydrates and an increase in the βoxidation of lipids. This metabolic shift is explained by a systemic attenuation of the insulin pathway, which is probably caused by abnormal mitochondria-ER contact as the result of too much or too little Gdap1 activity. We translate our Drosophila results to neuronal mammalian cell culture and demonstrate that over-expression of GDAP1 mutated forms cause an imbalance of insulin related proteins in basal conditions. Furthemore, we show that GDAP1 mutations trigger a blockage of the insulin response based in the inability to take glucose from the media after insulin treatment.
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