• Scientists have discovered a surprising mechanism by which the inherited genetic mutation known to cause Huntington’s disease leads to the death of brain cells. 

• The findings change the understanding of the fatal neurodegenerative disorder and suggest potential ways to delay or even prevent it.

• For 30 years, researchers have known that Huntington’s is caused by an inherited mutation in the Huntingtin (HTT) gene, but they didn’t know how the mutation causes brain cell death. 

• A new study published in Cell reveals that the inherited mutation doesn’t itself harm cells. Rather, the mutation is innocuous for decades but slowly morphs into a highly toxic form that then quickly kills the cell.

• The study was conducted in donated human brain tissue and led by scientists at Harvard Medical School, the Broad Institute of MIT and Harvard, and McLean Hospital. 

What is Huntington’s disease?

• Huntington’s disease is an inherited condition that causes brain cells to slowly lose function and die. 

• It is often passed down through a changed gene from a parent.

• It is caused by a mutation in the gene for a protein called huntingtin. The defect causes the building blocks of DNA called cytosine, adenine, and guanine (CAG) to repeat many more times than they normally do.

• It affects the cells in parts of the brain that regulate voluntary movement and memory. 

• The condition leads to dementia. 

• Common symptoms include uncontrollable movements and changes to thinking, behavior and personality. 

• It is a progressive condition that gets worse over time. 

• Adult-onset Huntington’s disease, the most common form of this disorder, usually appears in a person’s thirties or forties. 

• Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington’s disease develop involuntary jerking or twitching movements known as chorea. 

• As the disease progresses, these movements become more pronounced. Affected individuals may have trouble walking, speaking, and swallowing. 

• People with this disorder also experience changes in personality and a decline in thinking and reasoning abilities.

• Changes may include trouble with driving, prioritising (deciding which things are more important to do and which are less important), and organising, learning new things, remembering a fact, putting thoughts into words, or answering a question.

• These cognitive changes get worse as the disease progresses, until people with the condition are not able to work, drive, or care for themselves.

• A less common form of Huntington’s disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. 

Key Findings:

• Mutation Mechanism: The Huntington’s mutation involves a stretch of DNA in the HTT gene in which a three-letter sequence of DNA, “CAG”, is repeated at least 40 times, as opposed to the 15-35 repeats inherited by people without the disease. The researchers found that DNA tracts with 40 or more CAG repeats grow until they are hundreds of repeats long. This type of “somatic expansion” occurs in only the specific types of brain cells that later die in Huntington’s disease. Only once a cell's DNA expansion reaches a threshold number of CAGs — roughly 150 — does the cell sicken and then die. The cumulative death of many such cells leads to the symptoms of Huntington’s disease.

• Slow Expansion: The CAG repeats expand slowly over the first 20 years of life. After reaching around 80 repeats, the expansion accelerates, and once it surpasses 150 repeats, it becomes toxic, leading to neuronal death. This process happens over several decades, with symptoms of Huntington’s appearing in middle age.

• Cell-Specific Toxicity: Not all cells are affected the same way. Only striatal projection neurons (cells in the striatum, which is responsible for motor control and cognition) suffer from the toxicity, making these cells more susceptible to the mutation.

• Modeling CAG Repeat Expansion: Using computer modelling, the researchers estimated how and when CAG repeats expand in striatal projection neurons, which are primarily responsible for movement and cognition. This model suggests that neurons spend most of their life with the harmless mutation, and toxicity occurs only in a small fraction of cells after decades.

Implications for Treatment:

• New Treatment Strategies:The study’s findings could lead to new strategies for delaying or even preventing Huntington’s disease. Reducing CAG-repeat expansion or slowing the rate at which it expands could delay the onset of symptoms by preventing the toxicity that causes cell death.

• Previous Drug Trials: Drugs aimed at reducing the activity of the mutated gene have struggled, as they may only impact a small portion of affected cells. Targeting the mechanism that accelerates the CAG-repeat expansion could impact a larger number of cells, offering a more effective therapeutic approach.

• Broader Application: These insights could apply not just to Huntington’s but also to other genetic disorders involving abnormal DNA repeats, such as fragile X syndrome and myotonic dystrophy.

(The author is a trainer for Civil Services aspirants.)