OHSU Team Identifies Gene Essential for Brain's Protective Layer

Researchers at Oregon Health & Science University have discovered a gene that is critical to the brain’s ability to form myelin, a protective layer around nerves, potentially leading to new treatments for an extremely uncommon childhood disorder and more common diseases such as multiple sclerosis.

Image credit: Kateryna Kon/Shutterstock.com

The study, published in the Proceedings of the National Academy of Sciences, demonstrates that the gene transmembrane protein 63A, or TMEM63A, plays an important role in infantile hypomyelinating leukodystrophy 19, or HLD19, a rare genetic condition that disrupts brain development in early childhood.

Children with the condition frequently exhibit delayed development, coordination issues, and other neurological symptoms as a result of inadequate myelin, the protective layer that surrounds nerve cells.

This study employed mouse and zebrafish models to demonstrate that inactivating the TMEM63A gene causes early myelination deficits that closely resemble symptoms reported in children with HLD19. This study also explains how the majority of the gene alterations that produce HLD19 may prevent the gene from functioning correctly.

The hope is that if we understand how this gene facilitates myelination, then we can develop therapies that restore or promote myelin formation — not just for this rare disorder, but also for diseases like multiple sclerosis.

Swetha Murthy, PhD, Study Senior Author and Assistant Scientist, Vollum Institute, Oregon Health and Science University

“Our study identifies TMEM63A as a crucial regulator of myelin formation in the central nervous system. This discovery not only deepens our understanding of HLD19 but also provides powerful new models to guide future treatment strategies for related neurological disorders,” added Murthy.

Murthy became interested in the gene after initial reports linked it to HLD19 in children.

The gene’s function as a mechanosensitive ion channel, a protein that aids cells in reacting to mechanical stimuli, piqued her interest. She worked with Ben Emery, PhD, the Warren Distinguished Professor in Neuroscience Research and associate professor of neurology at the OHSU School of Medicine, and Kelly Monk, PhD, co-director and senior scientist at the Vollum Institute.

Both Monk and Emery investigate the role of myelin, albeit from different perspectives.

It’s been known for a long time that myelinating cells use physical cues such as the size of individual nerve fibers when they decide where to form their myelin, but how they sense those cues has remained a mystery. Swetha is an expert in the proteins that help cells sense the physical word around them, so Kelly and I were extremely excited to be able to work with her on this problem when she was recruited to OHSU. The fact this collaboration helps us understand the basis of an important childhood disease makes it even more gratifying.

Dr. Ben Emery, PhD, Warren Distinguished Professor and Associate Professor, Neuroscience Research, Neurology, School of Medicine, Oregon Health & Science University

While the role of TMEM63A in myelin production was previously unknown, the new study demonstrates that it is required for proper nervous system development.

“This gene senses mechanical pressure — a type of biological signal that has been overlooked in the context of myelination. We’re now showing that these mechanical signals may be essential for myelin-producing cells to properly wrap nerve fibers. This gives us a brand-new angle for understanding and potentially treating demyelinating diseases,” added Murthy.

Myelin is required for rapid, effective transmission among nerve cells. While demyelination in infants causes leukodystrophies such as HLD19, similar processes underpin multiple sclerosis, which affects over 2.8 million people worldwide, according to the National Multiple Sclerosis Society.

“We’ve shown that this gene’s effect on myelin is not only real — it’s conserved across species, including zebrafish and mice. That gives us powerful models to further study the disease and screen potential drug therapies,” stated Murthy.

The researchers now intend to delve deeper into how the gene influences the intricate cellular machinery involved in myelin production. This includes identifying other proteins that may work in tandem with it to help myelinating cells sense their physical surroundings in the brain.

“We're at the beginning of a new research direction. We want to understand the exact steps in myelin formation where this gene plays a role — and whether that process can be targeted with drugs. If so, it could reshape how we treat both rare leukodystrophies and more common conditions like MS,” further added Murthy.

The study is the outcome of a unique partnership between OHSU's Murthy, Monk, and Emery labs, which combine expertise in molecular biology, genetics, model organisms, and physiology.

“This kind of work is only possible in a highly collaborative environment like OHSU. Our team brought together different perspectives to tackle a challenging and meaningful problem. It's incredibly exciting to think about the long-term impact this could have on patients,” concluded Murthy.