In Huntington’s disease, proteins form toxic clumps that kill brain cells.
Storrs Institute for Medical Research
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Storrs Institute for Medical Research
In Huntington’s disease, proteins form toxic clumps that kill brain cells.
Storrs Institute for Medical Research
Diseases such as Alzheimer’s, Parkinson’s and Huntington’s are caused by toxic protein clumps that spread like forest fires through the brain.
Now, scientists say they have figured out how the ignition of at least one of the diseases starts. They also show how to turn it off.
The discovery concerns Huntington’s disease, a rare genetic brain disorder that shortened the life of songwriter Woody Guthrie. But the research has implications for other degenerative brain diseases, including Alzheimer’s.
Corinne Lasmézas, who studies neurodegenerative diseases at the Wertheim UF Scripps Institute in Jupiter, Fla., says it “opens the way” for finding the initial events that lead to diseases like Alzheimer’s and Parkinson’s . She was not involved in this study.
People with Huntington’s disease “start to lose control of their body movements, over time they develop mental disturbances, and eventually they die,” said study author Randal Halfmann, a researcher at the Storrs Institute for Medical Research in Kansas City, Missouri explain.
Like other neurodegenerative diseases, Huntington’s disease occurs when proteins in the brain fold into abnormal shapes and start sticking together. These abnormal protein clumps then start causing nearby proteins to misfold and clump together.
“As the disease progresses, you’re essentially looking at a forest fire,” Huffman said. “And you’re trying to figure out what started it.”
Essentially, Huffman’s team wanted to find the molecular matches that lead to the deadly flames.
look inside the cell
To do this, they need to record a fleeting and often invisible event. This is called nucleation, and the moment misfolded proteins begin to aggregate and multiply.
The team developed a method to perform the experiment within a single cell. They used genetic tweaks to create hundreds of fragments of the protein called PolyQ that become toxic in Huntington’s disease.
The team put different versions of PolyQ into a cell and looked for signs of misfolding and clumping.
“It’s a bit like you’re in a dark room and you’re trying to figure out the shape of the room,” Halfmann said. “You just keep bumping into stuff, and eventually you hit enough stuff to figure out what it’s like.”
The trial and error method worked, says Halfmann. “It’s a single PolyQ molecule that starts this little forest fire in the brain.”
Once the team identified the molecule, they were able to find a way to prevent its spread — at least in the lab. The trick is to flood the cells with the protein, actually extinguishing the flames before they can do any damage.
The next step, Halfmann said, will be to develop a drug that can have similar effects in humans.
“Ultimately, it only matters if we actually create a therapy,” he said. “Otherwise, it’s just schoolwork.”
The research could also lead to new treatments for other neurodegenerative diseases that prevent the cascade of events that lead to brain damage, Lasmézas said.
“You have to go back when the fire starts so it doesn’t spread throughout the forest,” she said.
Lessons from Alzheimer’s research?
The Alzheimer’s field appears to be learning its lesson.
Early drugs target the large amyloid plaques found in the brains of people with the disease. But the drugs didn’t work, perhaps because the plaque they were trying to remove was just the charred remains of forests that had already burned.
The newest drugs, such as lecanemab, still remove large clumps of amyloid, Lasmézas said, “but they also recognize the smaller, more toxic ones. That’s why they block neuronal toxicity more effectively.”
These smaller clumps form before the plaques appear and are closer to the events that initially trigger Alzheimer’s, Lasmézas said.
Studies like those in Huntington’s show that scientists are finally getting closer to strategies to slow or stop diseases including Parkinson’s and Alzheimer’s, Lasmézas said.
“For a long time, we knew very little about the mechanisms of neurodegenerative disease,” she said. “In the past, let’s say, 15 years, there has been a real explosion in knowledge.”
