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

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

Brain pathology (Zurich, Switzerland) (2020-06-09)
Stéphane Fourcade, Leire Goicoechea, Janani Parameswaran, Agatha Schlüter, Nathalie Launay, Montserrat Ruiz, Alexandre Seyer, Benoit Colsch, Noel Ylagan Calingasan, Isidre Ferrer, M Flint Beal, Frédéric Sedel, Aurora Pujol
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium bisulfite, ACS reagent
Sigma-Aldrich
Fluoromount Aqueous Mounting Medium, for use with fluorescent dye-stained tissues
Supelco
Supelclean LC-NH2 SPE Tube, bed wt. 500 mg, volume 3 mL, pk of 54
Sigma-Aldrich
Tetramethylrhodamine ethyl ester perchlorate, suitable for fluorescence, ≥90% (HPCE)