An expanding DNA stutter may hold the key to Huntington’s disease- unveiling why its symptoms appear midlife and differ from person to person.
- Huntington’s disease symptoms are linked to expanding DNA repeats (CAG) that become toxic in brain cells over time
- The "ticking DNA clock" accelerates after 80 repeats, killing neurons within months of reaching a critical threshold
- Targeting repair enzymes, like MSH3, offers new hope for treating even symptomatic Huntington’s patients
Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease
Go to source). Leslie Thompson, a neurologist at the University of California, Irvine who was not involved in the new study, calls the results "a remarkable insight." "This study, along with a few others, is altering our perspective on the illness."
The DNA "stutter" in Huntington’s disease can grow from 40 to over 1000 repeats in brain cells over a lifetime, turning toxic and killing neurons! #huntingtonsdisease #medindia’
Huntington's Disease: How Genetic Repeats Cause Devastating Effects
A defective form of the HTT gene, which codes for the protein huntingtin, is inherited by those who acquire Huntington's disease. A sequence of three nucleotide bases- cytosine, adenine, and guanine, or CAG in genetic jargon- is repeated several times in this gene's unique DNA segment.Additionally, individuals with 40 or more CAG repeats in the gene nearly invariably have symptoms later in life, including psychiatric and cognitive issues and uncontrollably jerking motions known as chorea, even though the majority of people inherit variants of HTT with 15 to 30 consecutive CAG repeats and never acquire Huntington's disease. A cluster of the huntingtin protein, which is excessively big and unstable, grows inside brain cells in people with hereditary stuttering. The illness typically results in early death, frequently by suicide, fall-related injuries, or problems with swallowing. The longer a person has a pattern of recurrent episodes, the sooner the condition manifests.
Unraveling Somatic Expansion: A Key to Huntington's Disease Progression
At first, researchers believed that the number of CAG repeats only rose as the HTT gene was inherited; a child of a parent with Huntington's disease may experience the disorder earlier in life. However, it turns out that the duration of this genetic "stutter" can vary in at least some of a person's cells throughout their lifetime. A 2003 study that examined brain samples from individuals who had passed away from Huntington's disease discovered startlingly huge CAG expansions in the striatum, a region of the brain. Huntington destroys this area, which is in charge of motivation and mobility. According to the authors, some expansions were up to 1000 repeats long and were impossible at birth (2✔ ✔Trusted SourceDramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis
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However, according to Sarah Hernandez, a Huntington researcher and head of research programs at the Hereditary Disease Foundation, that discovery "sat dormant" for years since researchers weren't certain how this process, known as somatic expansion, contributed to the condition.
According to Steve McCarroll, a geneticist and neuroscientist at the Broad Institute and co-senior author of the current Cell study, many experts believed that the disease was caused by prolonged exposure to the mutant huntingtin protein, with cells gradually becoming ill all at once.
Tracking the DNA Stutter: Insights from Single-Cell Analysis
McCarroll and his colleagues examined the RNA produced by the HTT gene, a marker of its activity, in hundreds of individual cells from postmortem brain tissue supplied by 50 individuals without Huntington's disease and 53 individuals with the disease to investigate how somatic expansion manifests in cells impacted by the disease. According to co-senior author Sabina Berretta, a neuroscience researcher at Harvard Medical School and McLean Hospital, the team was able to "dig … deep into the genetic and molecular changes" that underpin the condition thanks to the donated tissue.The researchers estimated how the cells evolved across their life spans using computer modeling and data from over 500,000 single cells. In the striatal neurons impacted by Huntington's disease, they found a distinct trajectory: The stutter develops gradually over two decades in cells with an HTT gene that has 40 or more CAG repeats. However, the sequence picks up new ones considerably more quickly after it reaches roughly 80 iterations. It approaches 150 repetitions in a few years, which seems to be a toxic threshold for some reason. According to the team, neurons quickly degrade- losing expression of important genes- and perish a few months after this "ticking DNA clock" runs out.
Midlife Onset and Variability: Decoding Huntington's Disease Patterns
The results may help explain why signs of the illness do not appear until midlife when many cells have reached the end of their useful lives. According to study co-author Seva Kashin, a software developer at Broad, damage spreads in a patchwork fashion throughout the striatum because different neurons accumulate repeats at different rates, with some crossing the deadly threshold earlier than others. This could account for the "huge variability" in how Huntington progresses in different individuals.According to Jeff Carroll, a Huntington researcher at the University of Washington who was not involved in the study, the current discovery "ties a bow" on decades of prior studies into somatic growth.
According to co-author Bob Handsaker, a geneticist at Broad, it is still unknown why this expansion quickens after 80 repetitions and turns lethal at 150, or why striatal neurons are especially susceptible to expanding repeats. Numerous cells in the body carry the HTT gene, and prior research has shown that Huntington's disease also damages other parts of the brain, albeit less severely than the striatum.
Targeting Repair Enzymes for Huntington's Disease Treatment
The study suggests possible therapeutic approaches. According to McCarroll, several studies have found enzymes that might be "complicit" in somatic expansion. Sometimes DNA fragments become lost during the transcription of HTT to produce protein, and these enzymes will mistakenly add more CAG repeats to fix the issue.An alternative to completely removing the mutant HTT protein, which has shown to be a difficult approach in clinical studies, is to target specific repair enzymes. (The authors of the new article remark that this might be because very few cells are producing a hazardous form of protein at any given moment.)
While none have progressed to human trials, several groups are attempting to inhibit one of these enzymes, known as MSH3, in animal models. Carroll points out that such enzyme-targeting therapies would theoretically be effective for patients who have previously experienced symptoms. "Even a sick person has 95% of their neurons that are rescuable because the HTT gene only becomes toxic late in a neuron's life."
Hernandez is enthusiastic about the possibility of treatments that diminish mutant huntingtin protein and target somatic expansion, as this dual strategy may optimize the therapeutic effect. The most fascinating aspect of the current study, she says, "is going to drive new theories to the clinic."
References:
- Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease - (https://www.cell.com/cell/fulltext/S0092-8674(24)01379-5)
- Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis - (https://academic.oup.com/hmg/article/12/24/3359/557823)
Source-Medindia