Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia.
(2015) Human Molecular Genetics — Vol. 24, n° 8, p. 2274-2286 (2015)
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- 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.
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Igoillo-Esteve, M., Gurgul-Convey, E., Hu, A., Romagueira Bichara Dos Santos, L., Abdulkarim, B., Chintawar, S., Marselli, L., Marchetti, P., Jonas, J.-C., Eizirik, D. L., Pandolfo, M., & Cnop, M. (2015). Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich’s ataxia. Human Molecular Genetics, 24(8), 2274-2286. https://doi.org/10.1093/hmg/ddu745 (Original work published 2015)