The dys-regulation of anti-oxidant defense via an impairment of Nrf2 response in the pathology of Friedreich’s ataxia

Shannon Chiang, Amy Anzovino, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang; Free Radical Biology and Medicine, Volume 120, Supplement 1, 20 May 2018, Pages S35 doi:10.1016/j.freeradbiomed.2018.04.120

The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.

The dys-regulation of anti-oxidant defense via an impairment of Nrf2 response in the pathology of Friedreich’s ataxia