期刊
BRAIN PATHOLOGY
卷 30, 期 5, 页码 945-963出版社
WILEY
DOI: 10.1111/bpa.12869
关键词
axonal degeneration; biotin; mTORC1; multiple sclerosis; NRF2; redox homeostasis; SREBP-1c
资金
- Medday Pharmaceuticals SA
- Autonomous Government of Catalonia [SGR 2014SGR1430, 2017SGR1206]
- Instituto de Salud Carlos III (European Regional Development Fund. ERDF, a way to build Europe) [PI17/00916]
- Instituto de Salud Carlos III (European Social Fund. ESF investing in your future) [CPII16/00016]
- Center for Biomedical Research on Rare Diseases (CIBERER)
- MedDay Pharmaceuticals
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.
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