Huntington’s and Alzheimer’s spread like fire in the brain. What turns them on? : Shots

1687168340 Huntingtons and Alzheimers spread like fire in the brain What | isentertainmentgroup

In Huntington’s disease, proteins form toxic clumps that kill brain cells.

Stowers Institute for Medical Research

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Stowers Institute for Medical Research

1687168338 442 Huntingtons and Alzheimers spread like fire in the brain What | isentertainmentgroup

In Huntington’s disease, proteins form toxic clumps that kill brain cells.

Stowers Institute for Medical Research

Diseases like Alzheimer’s, Parkinson’s and Huntington’s are caused by toxic clusters of proteins that spread through the brain like a forest fire.

Now scientists say they understand how fire starts in at least one of these diseases. They also showed how it can be extinguished.

THE find involves Huntington’s disease, a rare inherited brain disease that cut short the songwriter’s life Woody Guthrie. But the study has implications for other degenerative brain diseases, including Alzheimer’s.

‘Paves the way’ for finding the initiating event that leads to diseases like Alzheimer’s and Parkinson’s, says Corinne Lasmezas, who studies neurodegenerative diseases at the Wertheim UF Scripps Institute in Jupiter, Florida. She was not involved in the study.

People with Huntington’s « begin to lose control of their body movements, have mental impairments over time, and eventually die, » he says. Randall Halfmanstudy author and researcher at the Stowers Institute for Medical Research in Kansas City, Mo.

Like other neurodegenerative diseases, Huntington’s disease occurs when proteins in the brain fold into an abnormal shape and begin to stick together. Then these clumps of abnormal proteins start to cause the neighboring proteins to misfold and aggregate.

« As the disease progresses, you’re actually looking at some kind of forest fire, » says Halfmann. « And you’re trying to figure out what started it. »

Essentially, Halfmann’s team wanted to find the molecular match responsible for the lethal fire.

Looking inside a cell

To do this, they needed to narrate an event that is fleeting and usually invisible. Is called nucleationthe moment when a misfolded protein begins to aggregate and proliferate.

The team has developed a way to conduct experiments inside single cells. They used genetic modifications to create hundreds of versions of a protein segment called PolyQ, which becomes toxic in Huntington’s disease.

The team placed different versions of PolyQ in a cell, then looked for signs of misfolding and clumping.

« It’s kind of like you’re in a dark room and you’re trying to figure out what the shape of the room is, » says Halfmann. “You keep bumping into things and eventually you bump into things enough times to figure out exactly what they are like.”

The trial-and-error approach worked, Halfmann says. « What starts this little forest fire in the brain is a single molecule of PolyQ. »

Once the team identified that molecule, they were able to find a way to stop it from spreading, at least in the lab. The trick was to flood the cell with proteins which, in effect, smothered the flame before it could do any harm.

The next step is to develop a drug that can do something similar in people, Halfmann says.

« Ultimately, it only matters if we actually create therapy, » she says. « Otherwise, they’re just academics. »

The study could also lead to new treatments for other neurodegenerative diseases, says Lasmézas, treatments that prevent the cascade of events that lead to brain damage.

“You have to go back when the fire starts so it doesn’t spread all over the forest,” he says.

Lessons for Alzheimer’s research?

The Alzheimer’s camp seems to be learning that lesson.

The first drugs targeted the large amyloid plaques found in the brains of people with the disease. But these drugs haven’t worked, perhaps because the plaques they were trying to clear are just the charred remains of an already burned forest.

Lasmézas says newer drugs, such as lecanemab, still remove large clumps of amyloid, « but they also recognize smaller, more toxic ones. And that’s why they block neuronal toxicity more efficiently. »

These smaller lumps form before plaques appear and are closer to the event that triggers Alzheimer’s, Lasmézas says.

Studies like the one in Huntington’s show scientists are finally getting close to strategies that will slow or stop diseases including Parkinson’s and Alzheimer’s, says Lasmézas.

« For a long time, we didn’t know much about the mechanism of neurodegenerative diseases, » he says. « In the last, say, 15 years, there’s literally been an explosion of knowledge. »