Proteins in tiny cell tunnels may be Huntington’s treatment target
New study reveals how toxic huntingtin protein spreads through brain
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An interaction between two proteins — one called Rhes and the other Slc4a7 — helps to build tiny tunnels between nerve cells that allow mutant huntingtin protein, the cause of Huntington’s disease, to move from one neuron to another and spread throughout the brain.
Those are the findings of a new preclinical study, led by researchers at Florida Atlantic University (FAU), that highlight these two proteins as a treatment target in Huntington’s. The data showed that blocking Slc4a7 prevented the formation of these cellular highways and strongly reduced toxic huntingtin protein passage between nerve cells, both in lab-grown mouse cells and in mice.
The results imply that it may be possible to limit the spread of toxic huntingtin within the brain by targeting the Rhes-Slc4a7 signaling axis, according to the researchers.
“This work fundamentally changes how we think about disease progression in Huntington’s,” Srinivasa Subramaniam, PhD, the study’s senior author and an associate professor at the Charles E. Schmidt College of Science at FAU, said in a university news story detailing the research, which was done “using advanced protein-mapping techniques,” per the story.
“We’ve known that neurons somehow pass toxic proteins to one another, but now we can see the machinery that makes that possible,” Subramaniam said. “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.”
The study, “Membrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spread,” was published in the journal Science Advances.
Huntington’s is a genetic disorder marked by the production of a mutated version of the huntingtin protein, which is toxic to neurons. It’s previously been established that mutant huntingtin can spread from one nerve cell to a neighboring one through tunneling nanotubes, tiny structures that act like bridges to allow proteins to move from cell to cell.
Earlier studies have shown that the Rhes protein plays a key role in the formation of these cellular highways and in the transport of mutant huntingtin protein between neurons. Still, the details have not been clear.
Researchers focus on Rhes, Slc4a7 proteins using mouse models
This new study sheds more light on these processes, revealing that Slc4a7 — a protein best known for regulating the acidity inside cells — plays a key role.
Through a battery of tests in lab-grown mouse neurons and human cells, the researchers found that Rhes and Slc4a7 physically interact at the cells’ membrane, and that this interaction triggers a chain of molecular events that ultimately leads to the formation of a tunneling nanotube. Molecular cargo like mutant huntingtin can then flow through the tube, according to the researchers.
This research shines a spotlight on an entirely new way cells communicate in health and disease. … By learning how harmful proteins physically move from cell to cell, we gain powerful new leverage points for therapy.
When the scientists suppressed Slc4a7 in lab-grown mouse neurons and mice producing mutant huntingtin, the formation of these molecular tunnels was disrupted, and mutant huntingtin transfer between nerve cells was strongly reduced.
“This research shines a spotlight on an entirely new way cells communicate in health and disease,” said Randy Blakely, PhD, the executive director of the FAU Stiles-Nicholson Brain Institute, who was not involved in the study. “By learning how harmful proteins physically move from cell to cell, we gain powerful new leverage points for therapy.”
The researchers noted that tunneling nanotubes play a role not only in Huntington’s, but also in other neurological diseases and cancers.
“The idea that we could slow or even halt disease progression by blocking these microscopic tunnels opens an exciting frontier for treating not only Huntington’s disease, but a wide range of neurological disorders and cancers in the future,” Blakely said.
