Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination

Nature, 2018 · DOI: 10.1038/s41586-018-0360-3 · Published: August 1, 2018

Simple Explanation

The study identifies a mechanism for enhancing remyelination, the regeneration of the protective myelin sheath around nerve fibers, which is often damaged in neurological diseases like multiple sclerosis. Researchers found that small molecules promoting remyelination inhibit specific enzymes in the cholesterol biosynthesis pathway, leading to the accumulation of 8,9-unsaturated sterols. These accumulated sterols then act as a signal to promote the formation of new oligodendrocytes, the cells responsible for producing myelin, ultimately aiding in the remyelination process.

Study Duration

Not specified

Participants

Mouse models, human cells, human pluripotent stem cell-derived cortical spheroids

Evidence Level

Level: Not specified, Study type: In vitro and in vivo experiments

Key Findings

1
A broad range of pro-myelinating small molecules function by directly inhibiting CYP51, TM7SF2, or EBP, enzymes within the cholesterol biosynthesis pathway.
2
Accumulation of 8,9-unsaturated sterols is a key mechanistic node that promotes oligodendrocyte formation; these sterols are effective when supplied to OPCs, unlike analogous sterols lacking this structural feature.
3
Many previously reported enhancers of remyelination, such as benztropine, clemastine, tamoxifen, and U50488, induce accumulation of zymostenol and zymosterol, indicative of EBP inhibition in OPCs.

Research Summary

This study elucidates a unifying mechanism for small-molecule enhancers of oligodendrocyte formation: the elevation of 8,9-unsaturated sterol intermediate levels via inhibition of cholesterol biosynthesis enzymes CYP51, TM7SF2, and EBP. The accumulation of 8,9-unsaturated sterols in OPCs is identified as a central mechanism for enhancing oligodendrocyte formation, supported by the observation that nine independent 8,9-unsaturated sterols can enhance oligodendrocyte formation when supplied to OPCs. The findings demonstrate that modulating the sterol landscape in OPCs can enhance oligodendrocyte formation and points to new therapeutic targets and metabolite-based biomarkers for developing remyelinating therapeutics.

Practical Implications

Therapeutic Target Identification

CYP51, TM7SF2, and EBP are highlighted as potential therapeutic targets for developing remyelinating drugs.

Drug Development

The identified mechanism can be leveraged to develop more effective remyelinating therapies by focusing on molecules that induce the accumulation of 8,9-unsaturated sterols.

Biomarker Discovery

8,9-unsaturated sterols may serve as metabolite-based biomarkers to accelerate the development of optimal remyelinating therapeutics.

Study Limitations

1
The direct cellular targets of 8,9-unsaturated ‘meiosis-activating sterols’ remain poorly understood.
2
While the in vitro assays model the initial differentiation event into oligodendrocytes, the long-term effects and potential side effects of modulating sterol pathways require further investigation.
3
The study primarily focuses on mouse models, and further research is needed to fully validate the findings and optimize therapeutic strategies for human application.

Your Feedback

Was this summary helpful?

Back to Pharmacology