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Hum Mol Genet. 2015 Apr 15;24(8):2274-86. doi: 10.1093/hmg/ddu745. Epub 2014 Dec 30.

Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia.

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ULB Center for Diabetes Research and.
Institute of Clinical Biochemistry, Hannover Medical School, Hannover 30625, Germany.
Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels 1070, Belgium.
Institut de Recherche Expérimentale et Clinique, Pôle d' Endocrinologie, Diabète et Nutrition, Université Catholique de Louvain, Brussels 1200, Belgium.
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy and.
ULB Center for Diabetes Research and, Division of Endocrinology, Erasmus Hospital, 1070, Brussels, Belgium


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.

[Indexed for MEDLINE]

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