Rhes protein key in spread of Huntington’s disease in the brain
Pathogenic proteins help spread many neurodegenerative diseases. How they move between brain cells is often shrouded in mystery.
But scientists at Scripps Research’s Florida campus have found that nanotube tunnels that act like roadways capable of transporting cargo between cells can transmit a toxic protein linked to Huntington’s disease from neuron to neuron in the live brains of mouse models.
The finding is an important extension of work published by the same researchers in 2019 that demonstrated how the rhes protein triggered the construction of the nanotube tunnels in cell culture, thus revealing a mechanism allowing the toxic protein to spread in the brain and damage neurons.
The new study, published today in Science Advances, shows that blocking rhes could halt the spread of the toxic protein. The study’s senior author, Srinivasa Subramaniam, Ph.D., said the hope is that scientists might one day find a drug to essentially block that roadway, thereby hindering or halting the progression of the degenerative and irreversible neurological condition.
“We hope to screen molecules that can prevent the transport of toxic proteins in these tubes,” he said. “The future plan is to really target this protein.”
The discovery of the nanotube tunnels several years ago was a major step forward in understanding how Huntington’s disease attacks brain cells.
“The question after our 2019 study was, does this happen in real life? Can it move neuron to neuron in real brain where rhes is present?” said Subramaniam, an associate professor in the Department of Neuroscience at Scripps Florida. “We’ve now found that, yes, this protein can move between neurons in vivo,” or in the living brain of a mouse model.
Huntington’s disease begins in a part of the brain called the striatum, which is involved in processing voluntary movement. Previous human studies have shown that it progresses to the cortex.
Uri Nimrod Ramírez-Jarquín, Ph.D., the first author of the report and a postdoctoral associate in the Subramaniam lab, said he had not expected rhes to travel to the cortex.
“How did it travel there?” Ramírez-Jarquín asked. “There must be an active mechanism for protein transport between neurons, and our study demonstrates that.”
People with Huntington’s disease inherit a mutant gene that expresses a toxic protein that is complicit in damaging cells.
The striatum becomes atrophied and causes the eventual loss of motor control, cognitive deterioration and psychiatric disorders. Symptoms usually begin around age 30 to 40 and last 15 to 20 years, ending with the patient’s death. A more aggressive, less seen form of the disease affects children.
Huntington’s is rare, affecting 10 people out of 100,000 — mostly those of European ancestry, although it might be underreported in some places, such as India, Subramaniam said.
High-resolution imaging by Subramaniam’s team found that rhes moves via the nanotube tunnels between medium spiny neurons in the striatum of the intact mouse brain and then to the cortex.
“Now we have a model which indicates how such sequential events of degeneration may occur,” Subramaniam said. “The importance of this paper is the beautiful biology demonstrating how proteins move from one neuron to another. From a basic biology point of view, we have discovered a new connection, a new communication that can happen in the brain.”
The study required the development of new mouse models to track rhes in intact brain.
Subramaniam’s laboratory investigates the molecular mechanics of Huntington’s disease and other neurodegenerative illnesses, including Alzheimer’s and Parkinson’s diseases, to find potential therapy targets.
Four years ago, Subramaniam lab’s postdoctoral associate, Manish Sharma, Ph.D., looked at mouse neurons under a confocal microscope and saw that the cells formed sticky, string-like protrusions about 150 microns long that floated above the cells, connecting them.
It was a serendipitous discovery. Sharma had been doing live cell imaging to study endocytosis, a cellular process in which material is brought into the cell. The work was part of an effort to understand how rhes interacts with other proteins as movement occurs.
Sharma saw the protrusions and excitedly called Subramaniam over for a look. Subramaniam thought they looked like nanotube tunnels. How did he know? While working on his doctorate in 2004, a neighboring lab had been doing nanotube work.
“Nanotubes immediately came to mind,” Subramaniam said. “So, it was totally accidental.”
Their study subsequently tracked cell cargo moving through the nanotube tunnels after tagging the Huntington human disease protein with fluorescence and watching it cross between neurons in mouse brain cells.
They also saw that knocking out the rhes gene resulted in less brain damage. The protein exists in both human and mouse brains sickened with Huntington’s.
Future work will focus on how rhes builds these nanotube tunnels and helps transport the Huntington’s disease protein.
“A smart strategy would avoid destroying these tunnels, but stop the disease protein from entering into the tunnels,” said Subramaniam. “Such precise medicines will have more significant therapeutic potential to ameliorate Huntington’s disease. This is our goal.”
Besides Subramaniam, study co-authors are Uri Nimrod Ramírez-Jarquín, Manish Sharma, Neelam Shahani, Yuqing Li and Siddaraju Boregowda.
Research was supported by the National Institutes of Health (R01-NS087019-01A1, R01-NS094577-01A1), and by a grant from the CHDI Foundation.
The Florida-based branch of Scripps Research is integrating into the research arm of the University of Florida’s academic health center following an agreement reached last year.