Huntington’s disease is a genetic, neurodegenerative disorder that slowly causes patients to lose function and cognitive abilities; and experience memory and personality changes. The disorder ultimately leads to death about ten to twenty years after symptoms first arise. The only current treatments aim to manage symptoms but do not stop the progression of the fatal disorder. The disease has long been known to be caused by mutations in the huntingtin gene, which generates a toxic protein that spreads in the brain.
Scientists have now revealed more about how this toxic protein is passed from one brain cell to another. The work, which was reported in Science Advances, has shown that small structures that resemble tiny tubes link cells, allowing the toxic protein to move from one cell to another. The study has also shown that when these structures, known as tunneling nanotubes are disrupted, the toxic protein doesn’t spread through the brain as extensively.
Tunneling nanotubes can act like a direct physical link from one cell to another, without the need for signals. Although this kind of sharing could be important when tissues react to an injury or stress, it may become a problem in situations where a toxin is involved, such as in Huntington’s disease.
This study has also showed that a protein called Rhes, which is a known player in Huntington’s processes, can work with another molecule called SLC4A7, which aids in the regulation of internal acidity in cells. Rhes and SLC4A7 also help create tunneling nanotubes.
Rhes can link up with SLC4A7 at the cell membrane, triggering cellular changes that boost tunneling nanotube formation. When SLC4A7 was blocked with drugs or genetic tools in a mouse model of Huntington’s disease, nanotubes weren’t created and the toxic huntingtin protein barely spread.
“This work fundamentally changes how we think about disease progression in Huntington’s,” said senior study author Srinivasa Subramaniam, Ph.D., an associate professor at Florida Atlantic University. “We’ve known that neurons somehow pass toxic proteins to one another, but now we can see the machinery that makes that possible. By identifying SLC4A7 as a key partner of Rhes, we’ve uncovered a new and potentially druggable target to stop that spread at its source.”
Since tunneling nanotubes have also been observed in other neurodegenerative diseases, these findings may have implications for other disorders as well.
Sources: Florida Atlantic University, Science Advances