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Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts

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Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca2+ levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca2+ accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

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Acknowledgments

We wish to thank Doctor Luísa Cortes, head of Microscope Imaging Center of Coimbra (MICC) of CNC for the confocal image acquisition and analysis. This work was supported by “Fundação para a Ciência e Tecnologia” (FCT), Portugal, grants reference PTDC/SAU-FCF/66421/2006 and PTDC/SAU-FCF/108056/2008, and co-financed by COMPETE-“Programa Operacional Factores de Competitividade,” QREN, and the European Union (FEDER-“Fundo Europeu de Desenvolvimento Regional”). CNC is supported by project PEst-C/SAU/LA0001/2013-2014. L. Naia, M. Ribeiro, and M.J. Ribeiro are supported by Ph.D. fellowships from FCT (SFRH/BD/86655/2012, SFRH/BD/88983/2012, and SFRH/BD/41285/899/2007, respectively). T. Cunha-Oliveira, A.I. Duarte, T.R. Rosenstock, and M.N. Laço are supported by postdoctoral fellowships from FCT (SFRH/BPD/34711/2007, SFRH/BPD/26872/2006, SFRH/BPD/44246/2008, and SFRH/BPD/91811/2012, respectively).

Conflicts of Interest Statement

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal

    Luana Naia, I. Luísa Ferreira, Teresa Cunha-Oliveira, Ana I. Duarte, Márcio Ribeiro, Tatiana R. Rosenstock, Mário N. Laço, Maria J. Ribeiro, Catarina R. Oliveira & A. Cristina Rego

  2. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Luana Naia, Mário N. Laço, Catarina R. Oliveira & A. Cristina Rego

  3. Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Polo II, Coimbra, Portugal

    I. Luísa Ferreira, Teresa Cunha-Oliveira, Ana I. Duarte, Tatiana R. Rosenstock, Mário N. Laço, Catarina R. Oliveira & A. Cristina Rego

  4. Institut Curie, Orsay, 91405, France

    Frédéric Saudou & Sandrine Humbert

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  1. Luana Naia
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Correspondence to A. Cristina Rego.

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L. Naia and I. L. Ferreira contributed equally for this study.

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Naia, L., Ferreira, I.L., Cunha-Oliveira, T. et al. Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts. Mol Neurobiol 51, 331–348 (2015). https://doi.org/10.1007/s12035-014-8735-4

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