Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy.

ABSTRACT: The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3β. We find that GSK-3β inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1^- and Abcd1^-/Abcd2^-/- mice), ora

SUBMITTER: Ranea-Robles P 

PROVIDER: S-EPMC6079538 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature