Title | Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Ranea-Robles P, Launay N, Ruiz M, Calingasan NYlagan, Dumont M, Naudí A, Portero-Otín M, Pamplona R, Ferrer I, M Beal F, Fourcade S, Pujol A |
Journal | EMBO Mol Med |
Date Published | 2018 Jul 11 |
ISSN | 1757-4684 |
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 ( 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 ( and / 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 X-ALD 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-3β/NRF2 axis. |
DOI | 10.15252/emmm.201708604 |
Alternate Journal | EMBO Mol Med |
PubMed ID | 29997171 |