Aberrant regulation of the GSK-3b/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-3b. We find that GSK-3b inhibitors can significantly reactivate the blunted NRF2 response in patients’ fibroblasts. In the mouse models (Abcd1 and Abcd1 /Abcd2 / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 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 XALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK- 3b/NRF2 axis.

This study was supported by grants from the Spanish Institute for Health Carlos III and “Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa” [PFIS FI12/00457] to P.R-R., [FIS PI14/ 01115, FIS PI17/00134] to M.P.O., [FIS PI13/00584, FIS PI14/00328] to R.P., [FIS PI11/01043, FIS PI14/00410, FIS PI17/00916] to A.P., [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F.; the European Commission [FP7-241622] to A.P., the European Leukodystrophy Association [ELA2012-033C1] to A.P; the Autonomous Government of Catalonia [SGR 2017SGR696] to R.P. and [SGR 2014SGR1430; 2017SGR1206] to A.P.; and the Centre for Biomedical Research on Rare Diseases (CIBERER) to N.L. and M.R. Locomotor experiments were performed by the SEFALer unit F5 (CIBERER) led by A.P.