Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia
Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, Miriam Cnop
Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, Miriam Cnop
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Research Article Endocrinology Neuroscience

Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

Abstract

Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β cells. Exenatide induced frataxin and iron-sulfur cluster–containing proteins in β cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients’ induced pluripotent stem cell–derived β cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.

Authors

Mariana Igoillo-Esteve, Ana F. Oliveira, Cristina Cosentino, Federica Fantuzzi, Céline Demarez, Sanna Toivonen, Amélie Hu, Satyan Chintawar, Miguel Lopes, Nathalie Pachera, Ying Cai, Baroj Abdulkarim, Myriam Rai, Lorella Marselli, Piero Marchetti, Mohammad Tariq, Jean-Christophe Jonas, Marina Boscolo, Massimo Pandolfo, Décio L. Eizirik, Miriam Cnop

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Figure 2

Exenatide induces frataxin expression in KIKO mouse cerebrum and cerebellum and increases dorsal root ganglia neuronal cell area.

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Exenatide induces frataxin expression in KIKO mouse cerebrum and cerebel...
WT or KIKO mice were treated with saline (Veh) or exenatide (Ex) for 12 weeks. Frataxin protein in cerebrum (A–C) and cerebellum (D–F) was examined by Western blot (A, B, D, E) and mouse frataxin ELISA (C and F) (n = 5–12 per group). (A and D) Representative Western blot, where each lane corresponds to an independent mouse. (B and E) Densitometric quantification of the blots. Frataxin protein was normalized to the geometric mean of proteins GAPDH and α-tubulin (Western blot) or to total protein (ELISA). Data points correspond to individual mice. The median is shown by a horizontal line in the box plots; 25th and 75th percentiles are at the bottom and top of the boxes; and whiskers represent minimum and maximum values. *q < 0.05 Ex vs. Veh; #q < 0.05, and ##q < 0.01 KIKO vs. WT by Kruskal-Wallis test followed by Benjamini, Krieger, and Yekutieli correction for multiple comparisons. (G and H) Effect of exenatide on dorsal root ganglia neuronal area. (G) Representative image of a spine section and magnified dorsal root ganglia neurons (original magnification, ×4, and inset, ×10). (H) Distribution of dorsal root ganglia neuronal cell area (5–6 animals per group) measured by ImageJ (NIH) in WT and KIKO mice treated or not for 12 weeks with exenatide (10–23 pictures per group). The data are shown as a nonlinear fit of cell distribution. ***P < 0.001 Ex vs. Veh for comparison of the curves by nonlinear regression analysis using extra-sum-of-squares F test.