|Title||High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Fourcade S, Goicoechea L, Parameswaran J, Schlüter A, Launay N, Ruiz M, Seyer A, Colsch B, Calingasan NYlagan, Ferrer I, M Beal F, Sedel F, Pujol A|
|Date Published||2020 Jun 08|
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..
|Alternate Journal||Brain Pathol.|