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

EMBO Molecular Medicine
Pablo Ranea-RoblesAurora Pujol

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), 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 ...Continue Reading

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Citations

Oct 24, 2019·International Journal of Molecular Sciences·Sara PetrilloFiorella Piemonte
May 12, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Carlos CasasnovasAurora Pujol
Jul 10, 2020·Molecular and Cellular Biochemistry·Xinghan WuWentong Li
Jan 11, 2020·Cell Death & Disease·Sonia CiottiClaudio Brancolini
May 7, 2020·Biomolecules·Piergiorgio La RosaFiorella Piemonte
Dec 30, 2020·Journal of Inherited Metabolic Disease·Roberto MontoroMarc Engelen
Dec 5, 2020·World Journal of Biological Chemistry·Shruti V PalakuzhiyilSadanandavalli Retnaswami Chandra
Jan 13, 2022·The Journal of Cell Biology·Suzan KorsMichael Schrader

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Methods Mentioned

BETA
biopsies

Software Mentioned

SPSS
ImageJ
Cell
^ B
CONFIRM
Cell Counter ImageJ
ARRIVE
DEFINE

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