Tunneling nanotubes form connections between brain cells that express Rhes, a protein linked to Huntington’s disease.
Image Credit: Courtesy of Florida Atlantic University
Scientific Frontline: Extended "At a Glance" Summary: Tunneling Nanotubes in Huntington's Disease Progression
The Core Concept: Brain cells utilize microscopic, tube-like structures known as "tunneling nanotubes" to physically transfer toxic mutant huntingtin proteins to neighboring cells, thereby driving the progression of Huntington's disease.
Key Distinction/Mechanism: Unlike traditional chemical signaling that relies on diffusion across extracellular space, tunneling nanotubes function as direct, physical bridges that allow for the "hand-delivery" of cellular materials. The formation of these pathological highways is driven by a newly discovered molecular partnership at the cell membrane between the Rhes protein and SLC4A7, a bicarbonate transporter typically responsible for regulating internal cellular acidity.
Major Frameworks/Components:
- Tunneling Nanotubes: Microscopic cellular extensions that act as direct conduits for intercellular material transfer.
- Mutant Huntingtin Protein: The toxic biological material responsible for the cellular damage and death characteristic of Huntington's disease.
- Rhes Protein: A protein heavily implicated in Huntington's disease pathology that initiates structural cellular changes.
- SLC4A7 Transporter: A bicarbonate transporter that physically binds to Rhes to construct the nanotube infrastructure.
Branch of Science: Neuroscience, Molecular Biology, Cellular Biology, Biochemistry
Future Application: Identifying the Rhes-SLC4A7 partnership provides a highly specific, druggable target. Future pharmacological or genetic therapies could be engineered to block SLC4A7, thereby preventing nanotube formation and halting the physical spread of toxic proteins. Additionally, this intervention model may be adapted for other neurodegenerative disorders involving protein transfer (such as tauopathies) and certain cancers where tumor cells utilize similar structures to share energy or drug resistance.
Why It Matters: Huntington's disease currently has no cure, and existing treatments are limited to symptom management over a typical 10- to 20-year disease course. By revealing the exact mechanical infrastructure that allows the disease to spread across the striatum, this discovery shifts therapeutic focus from managing damage to actively containing and halting the underlying progression of the disorder at the cellular level.
Huntington’s disease is a devastating brain disorder that slowly robs people of movement, memory and personality. It is caused by a toxic protein that builds in brain cells and ultimately kills them. For years, scientists have known that this harmful protein doesn’t stay put – it spreads from one brain cell to another. However, exactly how that spread happens and how to stop it has remained a mystery.
In a major breakthrough, researchers from Florida Atlantic University and collaborators have identified a previously unknown cellular pathway that allows brain cells to pass toxic material directly to their neighbors through tiny, tube-like structures. Importantly, the study published in Science Advances, shows that disrupting this pathway dramatically reduces the spread of the disease-causing protein in the brain.
These microscopic structures, called “tunneling nanotubes,” act like direct bridges between cells. Unlike chemical signals that diffuse through space, nanotubes allow cells to share proteins and other materials by hand-delivery. While this kind of sharing may sometimes help healthy cells respond to stress or injury, it can also become dangerous when it spreads harmful proteins, like the mutant huntingtin protein responsible for Huntington’s disease.
The new research reveals that a protein called Rhes – already known to play a key role in Huntington’s disease – partners with an unexpected collaborator: a bicarbonate transporter called SLC4A7, a protein best known for helping cells regulate their internal acidity. Together, these two proteins help build tunneling nanotubes, creating highways that allow toxic huntingtin protein to move from one neuron to another.
“This work fundamentally changes how we think about disease progression in Huntington’s,” said Srinivasa Subramaniam, Ph.D., senior author, associate professor in the Department of Chemistry and Biochemistry within FAU’s Charles E. Schmidt College of Science, and a member of FAU’s Stiles-Nicholson Brain Institute, David and Lynn Nicholson Center for Neuroscience Research, and the Center for Molecular Biology and Biotechnology. “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.”
Using advanced protein-mapping techniques, the researchers discovered that Rhes physically binds to SLC4A7 at the cell membrane. When this partnership forms, it triggers changes inside the cell that promote the growth of nanotubes. When the team blocked SLC4A7 – either genetically or with drugs – the nanotubes failed to form, and the toxic huntingtin protein was largely unable to spread.
Significantly, this effect wasn’t just seen in isolated cells. In mouse models of Huntington’s disease, mice lacking SLC4A7 showed a dramatic reduction in the transfer of toxic protein between neurons in the brain’s striatum, the region most affected in the disease. This suggests that interfering with this newly discovered pathway could slow the progression of Huntington’s disease by containing the damage before it spreads.
The implications from this study extend far beyond Huntington’s disease. Tunneling nanotubes have been implicated in other neurodegenerative disorders, including conditions involving tau protein, as well as in cancer, where tumor cells use similar structures to share signals, energy and even drug resistance. Because both Rhes and SLC4A7 are involved in fundamental cellular processes, the newly identified pathway may represent a common mechanism underlying the spread of damage in many diseases.
“This research shines a spotlight on an entirely new way cells communicate in health and disease,” said Randy Blakely, Ph.D., executive director of the FAU Stiles-Nicholson Brain Institute, the David J.S. Nicholson Distinguished Professor in Neuroscience, and a professor of biomedical science in the FAU Charles E. Schmidt College of Medicine. “By learning how harmful proteins physically move from cell to cell, we gain powerful new leverage points for therapy. 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.”
As scientists continue to unravel how cells share information – and how that sharing can go wrong – this discovery offers new hope that stopping disease may one day be as simple as closing the door between cells.
Huntington’s disease is a rare, inherited brain disorder that affects about three to seven people per 100,000 worldwide and strikes men and women equally. Symptoms usually appear between the ages of 30 and 50 and worsen over time, causing uncontrolled movements, cognitive decline, and serious psychiatric symptoms. Each child of an affected parent has a 50 percent chance of inheriting the disease. There is no cure, and current treatments only help manage symptoms without stopping progression. After symptoms begin, people typically live 10 to 20 years, often facing increasing disability and loss of independence.
Additional information: Co-authors of the study represent the Facultad de Ciencias, National Autonomous University of Mexico; Institute of Cellular Physiology, National Autonomous University of Mexico; Max Planck Florida Institute for Neuroscience; and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology
Published in journal: Science Advances
Authors: Sunayana Dagar, Alexandra Fernandez, Uri Nimrod Ramírez-Jarquín, Violeta Gisselle Lopez-Huerta, Emaad Mirza, Chinmayee Mohapatra, Isabella Zuniga, Nicolai T. Urban, Gogce Crynen, George Tsaprailis, and Srinivasa Subramaniam
Source/Credit: Florida Atlantic University | Gisele Galoustian
Reference Number: ns032026_01