Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia
| العنوان: | Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia |
|---|---|
| المؤلفون: | Baroj Abdulkarim, Miriam Cnop, Marina Boscolo, Ana F Oliveira, Satyan Chintawar, Céline Demarez, Sanna Toivonen, Mohammad Tariq, Mariana Igoillo-Esteve, Miguel Lopes, Piero Marchetti, Decio L. Eizirik, Massimo Pandolfo, Myriam Rai, Amélie Hu, Federica Fantuzzi, Jean-Christophe Jonas, Ying Cai, Cristina Cosentino, Lorella Marselli, Nathalie Pachera |
| المساهمون: | UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition |
| المصدر: | JCI Insight, Vol. 5, no. 2, p. e134221 (2020) JCI Insight JCI insight |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Mitochondrion, Mice, Endocrinology, 0302 clinical medicine, Glucagon-Like Peptide 1, Cerebellum, Ganglia, Spinal, Insulin-Secreting Cells, Iron-Binding Proteins, Insulin, Glucose homeostasis, Gene Knock-In Techniques, Mice, Knockout, biology, Diabetes, Neurodegeneration, Brain, General Medicine, Middle Aged, Sciences bio-médicales et agricoles, Mitochondria, 3. Good health, 030220 oncology & carcinogenesis, Female, medicine.symptom, Research Article, medicine.drug, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Adolescent, Iron, Incretin, Neuroscience, Neuroprotection, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Aged, business.industry, medicine.disease, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, Gene Expression Regulation, Friedreich Ataxia, Frataxin, biology.protein, Exenatide, Reactive Oxygen Species, Trinucleotide Repeat Expansion, business |
| الوصف: | 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. info:eu-repo/semantics/published |
| وصف الملف: | 2 full-text file(s): application/pdf; application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::22b200b55a913111fdc37f52ecd11c1aTest https://hdl.handle.net/2078.1/225377Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....22b200b55a913111fdc37f52ecd11c1a |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |