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High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.

TitleHigh-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.
Publication TypeJournal Article
Year of Publication2020
AuthorsFourcade S, Goicoechea L, Parameswaran J, Schl├╝ter A, Launay N, Ruiz M, Seyer A, Colsch B, Calingasan NYlagan, Ferrer I, M Beal F, Sedel F, Pujol A
JournalBrain Pathol
Date Published2020 Jun 08
ISSN1750-3639
Abstract

Biotin is an essential cofactor for carboxylases that regulates 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 programme for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1 signalling. 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..

DOI10.1111/bpa.12869
Alternate JournalBrain Pathol.
PubMed ID32511826