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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.

Author information

1
ULB Center for Diabetes Research and.
2
Institute of Clinical Biochemistry, Hannover Medical School, Hannover 30625, Germany.
3
Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels 1070, Belgium.
4
Institut de Recherche Expérimentale et Clinique, Pôle d' Endocrinologie, Diabète et Nutrition, Université Catholique de Louvain, Brussels 1200, Belgium.
5
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy and.
6
ULB Center for Diabetes Research and, Division of Endocrinology, Erasmus Hospital, 1070, Brussels, Belgium mcnop@ulb.ac.be.

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.

PMID:
25552656
DOI:
10.1093/hmg/ddu745
[Indexed for MEDLINE]

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