A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration
Por:
V. DEL AMO, M. PALOMINO-SCHATZLEIN, M. SECO-CERVERA, J. GARCIA-GIMENEZ, F. PALLARDO, A. PINEDA-LUCENA and M. GALINDO
Publicada:
1 mar 2017
Resumen:
Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdapl gene. In order to get an overview about the changes that Gdapl mutations cause in our disease model, we have combined a comprehensive determination of the metabolic profile in the flies by nuclear magnetic resonance spectroscopy with gene expression analyses and biophysical tests. Our results revealed that both up- and down-regulation of Gdapl results in an early systemic inactivation of the insulin pathway before the onset of neuromuscular degeneration, followed by an accumulation of carbohydrates and an increase in the (3-oxidation of lipids. Our findings are in line with emerging reports of energy metabolism impairments linked to different types of neural pathologies caused by defective mitochondrial function, which is not surprising given the central role of mitochondria in the control of energy metabolism. The relationship of mitochondrial dynamics with metabolism during neurodegeneration opens new avenues to understand the cause of the disease, and for the discovery of new biomarkers and treatments. (C) 2017 Elsevier B.V. All rights reserved.
Filiaciones:
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Ctr Invest Principe Felipe, Valencia 46012, Spain
Ctr Biomed Network Res Rare Dis CIBERER, Valencia 46012, Spain
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Ctr Invest Principe Felipe, Valencia 46012, Spain
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Ctr Biomed Network Res Rare Dis CIBERER, Valencia 46012, Spain
Univ Valencia, Sch Med & Dent, INCLIVA Biomed Res Inst, Dept Physiol, Valencia 46010, Spain
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Ctr Biomed Network Res Rare Dis CIBERER, Valencia 46012, Spain
Univ Valencia, Sch Med & Dent, INCLIVA Biomed Res Inst, Dept Physiol, Valencia 46010, Spain
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Ctr Biomed Network Res Rare Dis CIBERER, Valencia 46012, Spain
Univ Valencia, Sch Med & Dent, INCLIVA Biomed Res Inst, Dept Physiol, Valencia 46010, Spain
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Ctr Invest Principe Felipe, Valencia 46012, Spain
Inst Invest Sanitaria La Fe, Drug Discovery Unit, Valencia 46026, Spain
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Ctr Invest Principe Felipe, Valencia 46012, Spain
Univ Politecn Valencia, IDM Inst Mol Recognit, Valencia 46022, Spain
UPV CIPF Joint Unit Dis Mech & Nanomed, Valencia, Spain
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