Surprising discovery sheds light on the cause of Huntington’s disease, a deadly brain disorder

Scientists are unraveling the mysteries that trigger Huntington’s disease. Huntington’s disease is a devastating and fatal genetic disease that occurs in early adulthood and causes nerve cells in some parts of the brain to be destroyed and die.

The genetic mutation associated with Huntington’s disease has long been known, but scientists didn’t understand why people can carry the mutation from birth and not develop the problem until later in life.

New research shows that, surprisingly, this mutation is harmless for several decades. But it silently grows into larger mutations that eventually cross a threshold, producing toxic proteins and killing the cells it proliferates.

“The challenge in our field is why, if the gene is present at conception, genetic diseases emerge later in life.” Albert Einstein College of Medicine’s Institute for Brain Disorders and Neural Regeneration said director Dr. Mark Mehler, who was not involved in the study. He called the study “groundbreaking” and said it “addresses many of the questions that have long plagued the field.”

Brain cell death eventually causes problems with movement, thinking, and behavior. Symptoms of Huntington disease (such as involuntary movements, unsteady gait, personality changes, and impaired judgment) usually begin between the ages of 30 and 50 and gradually worsen over 10 to 25 years.

Scientists at the Broad Institute of MIT and Harvard University, McLean Hospital in Massachusetts, and Harvard Medical School examined brain tissue donated by 53 Huntington’s disease patients and 50 non-Huntington’s patients, and found that 500,000 Cells were analyzed.

They focused on the Huntington mutation, which involves a set of DNA in which a three-letter sequence (CAG) is repeated at least 40 times within a particular gene. In people without the disease, this sequence is repeated only 15 to 35 times. They found that DNA tracts with more than 40 such “repeats” expanded over time to be hundreds of CAGs in length. When the CAG reaches a threshold of about 150, certain types of neurons become diseased and die.

The findings were “really surprising to us,” said Broad member Steve McCarroll, co-senior author of the study published Thursday in the journal Cell.

The researchers estimated that repeat tracts grow slowly during the first 20 years of life, then dramatically accelerate when they reach about 80 CAG.

“The longer the repetition, the earlier the onset occurs,” said neuroscience researcher Sabina Beretta, one of the study’s senior authors.

Previous research had found that repeat expansion in the range of 30 to 100 CAGs is necessary but not sufficient to cause Huntington’s disease, so when the findings were shared at the conference, some The researchers acknowledged that scientists were initially skeptical. McCarroll agreed that a CAG of 100 or less is not enough to cause disease, but said his research found that expansion by at least 150 CAG could cause disease.

Researchers hope their findings will help them come up with ways to slow or prevent this incurable disease, which affects about 41,000 Americans and currently takes medications to manage symptoms. I hope you find it helpful.

Recently, an experimental drug designed to reduce levels of a protein produced by a mutated Huntington gene has struggled in clinical trials. The new findings suggest that the reason is that very few cells carry the toxic protein at any given time.

Researchers said slowing or stopping the expansion of DNA repeats may be a better way to target the disease.

There’s no guarantee this will stop Huntington’s disease, but “many companies are starting or expanding programs to try to do this,” McCarroll said.

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