| First Author | Igoillo-Esteve M | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 2 | PubMed ID | 31877117 |
| Mgi Jnum | J:297727 | Mgi Id | MGI:6479193 |
| Doi | 10.1172/jci.insight.134221 | Citation | Igoillo-Esteve M, et al. (2020) Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight 5(2) |
| abstractText | 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 beta cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in beta 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 beta 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. |
