High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Brain Pathology Année : 2020

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

Stéphane Fourcade
  • Fonction : Auteur
Leire Goicoechea
  • Fonction : Auteur
Janani Parameswaran
  • Fonction : Auteur
Agatha Schlüter
Nathalie Launay
  • Fonction : Auteur
Montserrat Ruiz
  • Fonction : Auteur
Alexandre Seyer
  • Fonction : Auteur
Benoit Colsch
Noel Ylagan Calingasan
  • Fonction : Auteur
Isidre Ferrer
  • Fonction : Auteur
M. Flint Beal
  • Fonction : Auteur
Frédéric Sedel
  • Fonction : Auteur
Aurora Pujol

Résumé

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, theAbcd1(-)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.

Domaines

Neurosciences

Dates et versions

hal-03349346 , version 1 (20-09-2021)

Identifiants

Citer

Stéphane Fourcade, Leire Goicoechea, Janani Parameswaran, Agatha Schlüter, Nathalie Launay, et al.. High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy. Brain Pathology, 2020, 30 (5), pp.945-963. ⟨10.1111/bpa.12869⟩. ⟨hal-03349346⟩
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