High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy. (7th July 2020)

• Record Type: Journal Article
• Authors: Fourcade, Stéphane; Goicoechea, Leire; Parameswaran, Janani; Schlüter, Agatha; Launay, Nathalie; Ruiz, Montserrat; Seyer, Alexandre; Colsch, Benoit; Calingasan, Noel Ylagan; Ferrer, Isidre; Beal, M. Flint; Sedel, Frédéric; Pujol, Aurora
• Is Part Of: Brain pathology. Volume 30:Number 5(2020)
• Page Start: 945
• Page End: 963
• Publication Date: 2020-07-07
• Subjects: axonal degeneration -- biotin -- mTORC1 -- multiple sclerosis -- NRF2 -- redox homeostasis -- SREBP‐1c; Nervous system -- Diseases -- Periodicals; Brain -- Diseases -- Periodicals; Neurology -- Periodicals; Brain Diseases -- Periodicals; Cerveau -- Maladies -- Périodiques; Système nerveux -- Maladies -- Périodiques; Neurologie -- Périodiques; 616.805
• DOI: 10.1111/bpa.12869
• Languages: English
• ISSNs: 1015-6305

Abstract

Abstract: Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high‐dose pharmaceutical‐grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high‐dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1 − mouse model of adrenomyeloneuropathy. High‐dose biotin restored redox homeostasis driven by NRF‐2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP‐1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High‐dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high‐dose biotin of relevance for neurodegenerative and metabolic disorders.