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

• Published in: EMBO molecular medicine Vol. 10; no. 8
• Main Authors: Ranea‐Robles, Pablo, Launay, Nathalie, Ruiz, Montserrat, Calingasan, Noel Ylagan, Dumont, Magali, Naudí, Alba, Portero‐Otín, Manuel, Pamplona, Reinald, Ferrer, Isidre, Beal, M Flint, Fourcade, Stéphane, Pujol, Aurora
• Format: Journal Article
• Language: English
• Published: England EMBO Press 01.08.2018; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: adrenoleukodystrophy; Antioxidants; dimethyl fumarate; Glicogen; Glycogen; GSK‐3; Life Sciences; Metabolism; Metabolisme; Neurobiology; Neurons and Cognition; NRF2; oxidative stress; Therapeutic use; Ús terapèutic; GSK‐3; dimethyl fumarate; NRF2; adrenoleukodystrophy; oxidative stress
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201708604

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), 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. Synopsis This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option. NRF2‐mediated antioxidant response is impaired in X‐linked adrenoleukodystrophy (X‐ALD) mouse spinal cord and human fibroblasts. Aberrant GSK‐3β activity is responsible for the NRF2 blunted response against oxidative stress in X‐ALD fibroblasts. Molecular defects present in the X‐ALD mouse model are rescued after oral treatment with dimethyl fumarate, an NRF2 activator in current use for multiple sclerosis. Axonal degeneration and locomotor impairment in X‐ALD mouse model are prevented with dimethyl fumarate, indicating its therapeutic potential for X‐ALD patients. This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option.