Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy.
作者： Pablo Ranea‐Robles , Nathalie Launay , Montserrat Ruiz , Noel Ylagan Calingasan , Magali Dumont
关键词: Peroxisome 、 GSK-3 、 Cell biology 、 Inflammation 、 Reactive oxygen species 、 Chemistry 、 Adrenoleukodystrophy 、 Oxidative stress 、 Mitochondrial depletion 、 Dimethyl fumarate
摘要: The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients mouse model (Abcd1 null mouse). This rare neurometabolic disease caused by loss function peroxisomal transporter ABCD1, leading to an accumulation very long-chain fatty acids induction reactive oxygen species mitochondrial origin. Here, we identify impaired NRF2 response aberrant activity GSK-3β. We find that GSK-3β inhibitors can significantly reactivate blunted patients' fibroblasts. In models (Abcd1- Abcd1-/Abcd2-/- mice), oral administration dimethyl fumarate (DMF/BG12/Tecfidera), activator use for multiple sclerosis, normalized (i) depletion, (ii) bioenergetic failure, (iii) oxidative damage, (iv) inflammation, highlighting intricate cross-talk governing energetic redox homeostasis X-ALD Importantly, DMF halted axonal degeneration locomotor disability suggesting therapies activating hold therapeutic potential other axonopathies with GSK-3β/NRF2 axis.
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