title: Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA) is a neurodegenerative disorder associated with cardiomyopathy and diabetes. Effective therapies for FRDA are an urgent unmet need; there are currently no options to prevent or treat this orphan disease. FRDA is caused by reduced expression of the mitochondrial protein frataxin. We have previously demonstrated that pancreatic β-cell dysfunction and death cause diabetes in FRDA. This is secondary to mitochondrial dysfunction and apoptosis but the underlying molecular mechanisms are not known. Here we show that β-cell demise in frataxin deficiency is the consequence of oxidative stress-mediated activation of the intrinsic pathway of apoptosis. The pro-apoptotic Bcl-2 family members Bad, DP5 and Bim are the key mediators of frataxin deficiency-induced β-cell death. Importantly, the intrinsic pathway of apoptosis is also activated in FRDA patients' induced pluripotent stem cell-derived neurons. Interestingly, cAMP induction normalizes mitochondrial oxidative status and fully prevents activation of the intrinsic pathway of apoptosis in frataxin-deficient β-cells and neurons. This preclinical study suggests that incretin analogs hold potential to prevent/delay both diabetes and neurodegeneration in FRDA.
authors.affiliation: ULB Center for Diabetes Research and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gurgul-Convey
authors.affiliation: Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels 1070, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Hu
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle d' Endocrinologie, Diabète et Nutrition, Université Catholique de Louvain, Brussels 1200, Belgium.
authors.forename: Laila
authors.initials: L
authors.lastname: Romagueira Bichara Dos Santos
authors.affiliation: ULB Center for Diabetes Research and.
authors.forename: Baroj
authors.initials: B
authors.lastname: Abdulkarim
authors.affiliation: Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels 1070, Belgium.
authors.forename: Satyan
authors.initials: S
authors.lastname: Chintawar
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy and.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy and.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle d' Endocrinologie, Diabète et Nutrition, Université Catholique de Louvain, Brussels 1200, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Jonas
authors.affiliation: ULB Center for Diabetes Research and.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels 1070, Belgium.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.affiliation: ULB Center for Diabetes Research and, Division of Endocrinology, Erasmus Hospital, 1070, Brussels, Belgium mcnop@ulb.ac.be.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005621:Friedreich Ataxia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin