par Igoillo Esteve, Mariana ;Martins Oliveira, Ana Filipa ;Cosentino, Cristina ;Fantuzzi, Federica ;Demarez, Céline ;Toivonen, Sanna ;Hu, Amelie ;Chintawar, Satyan ;Lopes, Miguel ;Pachera, Nathalie ;Cai, Ying ;Abdulkarim, Baroj ;Rai, Myriam ;Marselli, Lorella;Marchetti, Piero;Tariq, Mohammad;Jonas, Jean-Christophe JJC;Boscolo, Marina ;Pandolfo, Massimo ;Eizirik, Decio L. ;Cnop, Miriam
Référence JCI insight
Publication Publié, 2019-12-01
Référence JCI insight
Publication Publié, 2019-12-01
Article révisé par les pairs
Résumé : | 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 Friedreich ataxia patients. 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. |