Aberrant regulation of the GSK ‐3β/ NRF 2 axis unveils a novel therapy for adrenoleukodystrophy

The nuclear factor erythroid 2‐like 2 ( NRF 2) 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 ABCD 1, 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 NRF 2 response caused by aberrant activity of GSK ‐3β. We find that GSK ‐3β inhibitors can significantly reactivate the blunted NRF 2 response in patients’ fibroblasts. In the mouse models ( Abcd1 − and Abcd1 − / Abcd2 −/− mice), oral administration of dimethyl fumarate ( DMF / BG 12/Tecfidera), an NRF 2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross‐talk governing energetic and redox homeostasis in X‐ ALD . Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF 2 hold therapeutic potential for X‐ ALD and other axonopathies with impaired GSK ‐3β/ NRF 2 axis.