Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

• DOI: 10.1172/jci.insight.134221
• Publication Date: 2019-12-26T17:03:51Z
• Authors: Mariana Igoillo-E...; 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 J...; Marina Boscolo; Massimo Pandolfo; Décio L. Eizirik; Miriam Cnop
• Keywords: Adult; Male; 0301 basic medicine; 570; Adolescent; Iron; 610; Diabete; Diabetes; Endocrinology; Mitochondria; Neurodegeneration; Neuroscience; 03 medical and health sciences; Endocrinology; Glucagon-Like Peptide 1; Cerebellum; Ganglia, Spinal; Insulin-Secreting Cells; Iron-Binding Proteins; Animals; Humans; Insulin; Gene Knock-In Techniques; Neurodegeneration; Aged; Diabetes; Brain; Sciences bio-médicales et agricoles; Mitochondria; 3. Good health; Disease Models, Animal; Gene Expression Regulation; Friedreich Ataxia; Exenatide; Female; Neuroscience

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.