Rhes Protein Builds Tunnels That Transport Huntington Disease Driver, Study Finds

Mutant huntingtin, the protein involved in Huntington’s disease, travels from one neuron to another using a network of tunnels built by a protein called Rhes, a study finds.

The study, “Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion,” was published in the Journal of Cell Biology.

Huntington’s disease is characterized by the abnormal production and accumulation of a protein called huntingtin, which is broken down into small pieces that stick together and form toxic protein aggregates inside nerve cells. These aggregates gradually disrupt the function of these nerve cells and, ultimately, lead to their death.

Previous studies have suggested that mutant huntingtin (mHTT) may spread throughout the brain by traveling from one neuron to another. This hypothesis has been backed up by data from studies performed in animal models of the disease, but the mechanism responsible for the transport of mHTT between neurons and also for the massive loss of nerve cells in the striatum (a region of the brain responsible for movement control) is still poorly understood.

“Previously, we linked Rhes, a small [protein] highly enriched in the striatum, to striatal cell loss in HD [Huntington’s disease],” the investigators wrote.

Researchers at The Scripps Research Institute in California have now found that Rhes is responsible for the formation of small tubes, called tunneling nanotubes (TNT), that mHTT uses to travel between neurons until it reaches specific areas of the brain.

“We are excited about this result because it may explain why the patient gets the disease in this area of the brain called the striatum,” Srinivasa Subramaniam, PhD, an associate professor in the department of neuroscience at Scripps Research-Florida, said in a press release.

The discovery was made after scientists looked at mouse neurons under a high-resolution confocal microscope that allows them to visualize cellular structures at different planes of depth, and spotted small string-like protrusions connecting different neurons.

To find out whether mHTT was indeed using this network of tunnels built by Rhes to travel between neurons, the researchers placed a fluorescent-labeled version of the human mHTT protein inside mouse neurons to follow its trajectory.

When they did so, they saw that human mHTT traveled from neuron to its neighbouring nerve cell using the TNTs as if they were a bridge connecting two patches of land in a lake. Once mHTT reached the second neuron safely, the TNT disappeared.

According to the team, TNTs are also involved in the transport of other types of cargo between cells, including lysosomes and endosomes (small cell compartments that digest and recycle several molecules).

“The Rhes protein makes its own road. That is what is surprising to us,” Subramaniam said. “But it not only transports itself. Once the road is made, many things can be transported.”

Next steps in the investigation will include exploring the role of other proteins besides Rhes that may be involved in the transport of mHTT, as well as other medical conditions for which this mechanism may be relevant.

“A recent study indicates Rhes also mediates Tau pathology in an Alzheimer’s disease mouse model,” the researchers wrote, noting that although they did not observe normal Tau being transported by Rhes tunnels, it may be a possibility to be tested in mice.

“Also, studies on mHTT transport via Rhes tunnels will generate a new perspective in understanding of the mechanisms of striatal vulnerability in [Huntington’s disease], which may lead to the novel therapeutic opportunities to block the cell-cell movement of mHTT by Rhes, and thus, [Huntington’s disease] progression,” they added.