Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia
2014; Oxford University Press; Volume: 24; Issue: 8 Linguagem: Inglês
10.1093/hmg/ddu745
ISSN1460-2083
AutoresMariana Igoillo‐Esteve, Ewa Gurgul-Convey, Amelié Hu, Laila R.B. Santos, Baroj Abdulkarim, Satyan Chintawar, Lorella Marselli, Piero Marchetti, Jean‐Christophe Jonas, Décio L. Eizirik, Massimo Pandolfo, Miriam Cnop,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoFriedreich'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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