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 5

Exenatide alleviates oxidative stress and mitochondrial dysfunction in FRDA patients’ iPSC-derived sensory neurons.

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Exenatide alleviates oxidative stress and mitochondrial dysfunction in F...
Sensory neurons were differentiated from iPSCs from 2 healthy controls (CT1 and CT2) and 2 patients with FRDA (FA135 Cl1 and HEL135.2). At the end of differentiation cells were treated for 72 hours with PBS (Veh) or exenatide (Ex, 500 nM) in neurobasal medium. (A) Representative immunofluorescence of CT1 cells during sensory neuron differentiation (images are representative of 7 similar experiments; more images are shown in Supplemental Figure 7A). Pictures were taken at original magnification ×20. Expression of sensory neuron markers Brn3a and peripherin was examined at day 8 and neuron-specific cytoskeleton marker β-tubulin III at day 8 and after 72-hour culture in neurobasal medium (NB). (B) Frataxin protein expression was analyzed by ELISA and normalized to total protein (n = 4–6 per group). (C) Oxidative stress was measured with hydroxyphenyl fluorescein (HPF) probe. (D–G) Mitochondrial respiration was assessed by XFp Extracellular Flux Analyzer (Seahorse, n = 5–7 per group). (D) Oxygen consumption rate (OCR) profiles of control and FRDA patients’ sensory neurons in basal condition and after injection (arrows) of the ATP synthase inhibitor oligomycin, the mitochondrial uncoupler FCCP, and the metabolic poisons rotenone and antimycin A. (E–G) OCR measures were used to calculate basal respiration, ATP production, and maximal respiratory capacity. The horizontal line in the box corresponds to the median; 25th and 75th percentiles are at the bottom and top of the boxes; and whiskers indicate minimum and maximum values. Data points represent independent experiments. Patients are shown in different colors; the smaller GAA expansion size in FXN is shown in brackets. #P < 0.05, and ##P < 0.01 CT vs. FRDA Veh by unpaired 2-tailed t test; *P < 0.05, and **P < 0.01 FRDA Veh vs. FRDA Ex 500 by paired 2-tailed t test.