High Biotin Doses Restore Nerve Cell Health in ALD Mice, Study Shows

High Biotin Doses Restore Nerve Cell Health in ALD Mice, Study Shows
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High doses of the B vitamin biotin restored metabolic balance and rescued nerve degradation in a mouse model of adrenoleukodystrophy (ALD), a study found.

Based on the finding, the researchers suggest high-dose biotin treatment may be a therapeutic option for people with ALD.

The study, “High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy,” was published in the journal Brain Pathology.

ALD is caused by mutations in the ABCD1 gene, which carries instructions for the production of the adrenoleukodystrophy protein (ALDP). A deficiency in ALDP leads to the abnormal buildup of very long-chain fatty acids (VLCFAs) that, in excess, destroys the myelin sheath, which is the protective covering that insulates nerve cells.

Another disease characterized by myelin sheath destruction is multiple sclerosis (MS), in which myelin degradation is caused by a mistaken attack by the immune system. 

A placebo-controlled clinical trial demonstrated that a subset of MS patients treated with high doses of biotin (vitamin B7) led to a sustained reversal of MS-related disability. The doses used were 10,000 times higher than the daily recommended dietary intake. 

Those findings prompted researchers based at the Bellvitge Biomedical Research Institute (IDIBELL) in Spain to investigate the underlying mechanism of high-dose biotin treatment as a first step to support its application to other neurodegenerative diseases such as ALD.

The team used a mouse model of ALD in which the ABCD1 gene had been mutated to mimic the condition. These mice develop nerve damage and motor impairment later in life, which resembles the form of ALD known as adrenomyeloneuropathy (AMN).

A second mouse model was used in which the ABCD1 gene and the similar ABCD2 gene were mutated. Because the ABCD2 gene can partially compensate for the ABCD1 gene mutations, mice with both mutations develop a more substantial accumulation of VLCFAs and more severe, earlier onset nerve damage.

Research using the double mutant ALD mice led to the discovery that nerve damage is accompanied by problems with mitochondria — the small structures in the cell that produce chemical energy in the form of ATP. 

A consequence of VLCFA buildup is the generation of reactive oxygen species (ROS) in the mitochondria, which are unstable molecules that readily react and damage other molecules and tissues. 

In an initial experiment, cells from ALD patients were exposed to increasing doses of biotin, which successfully prevented mitochondrial ROS production caused by a reactivation of a signaling pathway called NRF2, which functions to reduce oxidative stress.

Based on the results, the single mutant ABCD1 mice were exposed to biotin doses that match those used in MS patients. This treatment normalized the NRF2 pathway and also increased the numbers of mitochondria and ATP levels, both of which are decreased in ALD. 

The double mutant mice (ABCD1/ABCD2) were treated with high biotin doses for six months and then challenged with three motor tests. In two tests, motor abnormalities were eliminated in treated mice as they performed in a similar way as healthy control mice. Likewise, high-dose biotin treatment prevented nerve cell damage in these animals. 

“High-dose biotin rescued locomotor deficits in Abcd1-/Abcd2-/- mice” and also “prevents axonal damage,” the researchers wrote.

An examination of lipid (fat) profiles in the spinal cord of double mutant mice found high levels of lipid buildup with about half reaching statistical significance. The levels of all of these different lipids were normalized by treatment with high-dose biotin.

Lipids in cells are stored as droplets and were shown to accumulate in motor neurons of double mutant mice. Six months of high-dose biotin treatment normalized the numbers and size of these lipid droplets. 

Finally, experiments showed that the origin of increased lipids in the spinal cord of these mice was triggered by the activation of genes involved in lipid production. Biotin treatment reduced this activation and also activated genes involved in lipid degradation, thus restoring balance. 

“These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders,” the researchers wrote. 

“Taken together, our findings strongly suggest that interventional treatment using high-dose biotin may be an attractive therapeutic option for patients with [AMN],” they added. 

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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