Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 8, Pages 2274-2286Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu745
Keywords
-
Funding
- Fonds Erasme Olivia De Clercq, Belgium
- Phillip Bennett and Kyle Bryant Translational Research Award of the Friedreich Ataxia Research Alliance, USA
- European Union (European Community)
- Actions de Recherche Concertee de la Communaute Francaise (ARC)
- Fonds National de la Recherche Scientifique (FNRS), Belgium
Ask authors/readers for more resources
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 beta-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 beta-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 beta-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 beta-cells and neurons. This preclinical study suggests that incretin analogs hold potential to prevent/delay both diabetes and neurodegeneration in FRDA.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available