One mystery that many scientists think holds the key to curing HD is its mysterious age of onset. Although people with HD carry the expanded gene from birth, they generally don’t develop symptoms until later in life, suggesting something bad is brewing beneath the surface! One explanation, which has gained significant traction in recent years, is a process called somatic instability, where the expansion worsens over a person’s life. Recent work from the lab of Dr. Jeff Carroll at the University of Washington investigated several genetic techniques to understand what causes somatic instability and whether huntingtin-lowering therapeutics might slow it down. 

An Unstable Repeat

To understand somatic instability, let’s briefly revisit how genes work. Normally, genes like huntingtin, or HTT, are copied to make messenger molecules, called mRNA, through a process known as transcription. These genetic messages can then be used as a template to make proteins through another process called translation. 

However, in HD, the HTT gene contains extra genetic letters (C-A-Gs) that repeat too many times, causing its mRNA message to create an abnormal protein. In some cells, these repeating CAGs can grow even longer over someone’s life, leading to mRNA that is increasingly repetitive. By the time symptoms appear, these CAG repeats may have grown into the hundreds in certain cells. The continuously expanding CAG repeat in HTT, called somatic instability, is a leading theory for why the onset of HD is typically delayed into adulthood. 

Many ongoing clinical trials are focused on reducing the amount of HTT produced from the faulty gene. However, it’s unclear if lowering HTT levels will slow down the growth of the CAG repeat in the HTT gene. Although somatic instability is a prime suspect for causing HD’s delayed onset, it’s still only a correlation. Regardless, it’s certainly worth investigating what causes it and whether HTT-lowering therapies, which are already in clinical trials, can affect it. 

Dialling Down Huntingtin 

In a new study, a team at the University of Washington tested whether HTT lowering affects somatic instability. From previous work, they had used a type of therapy called Antisense Oligonucleotides (ASOs), which bind mRNA and send it to the cell’s trash can, to lower HTT levels in mice. They followed up on these experiments and discovered that ASOs also reduced CAG repeat growth by about 50%. This is good news because several ongoing clinical trials are already investigating ASOs.

Although the ability of ASOs to reduce target mRNA levels is well understood, the researchers were surprised that it stunted the growth of CAGs in the HTT gene. They suspected the ASOs might also disrupt mRNA at its source – a process called transcription. Recent work by other groups has linked rates of transcription with the growth of CAGs, such that the more the HTT gene is used to make mRNA, the quicker the CAGs build up. This hypothesis led the team to investigate exactly how ASOs were slowing CAG growth. 

The researchers considered two possible ways ASOs might be slowing somatic instability. 

1. The HTT protein itself was responsible for somatic instability, and by reducing the production of HTT, ASOs reduced somatic instability. 
2. The process of switching on the HTT gene was causing somatic instability, and by reducing transcription, ASOs reduced somatic instability. 

To find out how ASOs might affect somatic instability, the researchers injected a similar molecule into mice, called siRNA, which reduces HTT protein but does not affect transcription. When HTT protein levels were lowered using siRNA, they did not see any effect on somatic instability. This doesn’t mean siRNA wasn’t exerting a beneficial effect, just that siRNA wasn’t reducing somatic instability in the cells the team looked at. However, it does indicate that ASOs are slowing CAG growth by disrupting transcription, and not by lowering protein levels. 

Fewer Deliveries, Less Potholes?

To visualize the difference between siRNA and ASOs, imagine the HTT gene as an old road traveled by semi-trucks making deliveries, and the packages represent mRNA messages. With each year that the road is driven on, its potholes and cracks worsen, just as HTT’s CAG repeat worsens the more it’s used to make protein. Reducing HTT levels with siRNA is like reducing the number of packages, but the same number of trucks are still on the road – they are just emptier! ASOs, however, reduce the number of trucks, and fewer trucks mean less wear and tear on the road, and thus slower CAG growth. 

The researchers tried a more direct approach to test the connection between somatic instability and transcription. They turned to a genetically modified mouse model of HD where HTT transcription can be switched on or off, like a switch, by adding a special chemical to their drinking water. In mice where HTT transcription was switched off, they observed somatic instability slowing down. In addition, the longer HTT transcription was turned off, the less the CAG repeats grew. These results, in addition to their ASO experiments, provided good evidence that transcription was partially responsible for somatic instability. 

Zinc Finger Roadblocks

Although switching HTT on or off by adding a chemical to drinking water sounds fantastic, it only works in this specific type of genetically modified mice, which we sadly are not! So the researchers turned to a more practical approach using Zinc Finger Proteins (ZFPs), which are genetically modified proteins that attach directly onto CAG repeats and block transcription. From our analogy, ZFPs are like giant roadblocks cutting off traffic. If the delivery trucks driving over the road (representing transcription) are causing the potholes to worsen (CAG growth), then halting the traffic should slow somatic instability. 

To test ZFPs, they used a virus to deliver their DNA instructions into mouse brains. One side of the mouse’s brain got a version of the ZFP that latches onto the CAG repeat and shuts down transcription, and the other side got a version of the ZFP that binds HTT but does not shut down transcription. The ZFPs that block transcription showed an impressive 70% reduction in somatic instability. Surprisingly, ZFPs that bind to HTT but don’t block transcription still had a modest 42% reduction in somatic instability. This is good news because completely shutting down HTT transcription might be unsafe because HTT still performs important functions inside brain cells. So keeping HTT partially on while slowing somatic instability might represent a safer therapeutic approach. 

Therapeutic Directions

Collectively, these results show that dialing down HTT’s transcription not only reduces the amount of toxic HTT protein in the cell but might also slow its CAG growth. Although slowing CAG growth sounds like a home run, it’s important to reiterate that we still don’t know for sure if somatic instability is causing disease onset – it’s just a promising lead! In addition, reducing HTT transcription, which was linked to slowed somatic instability, might cause entirely unrelated problems in the cell. In our analogy, blocking package deliveries would stop the potholes from forming, but this would also surely create an angry bunch of customers waiting for their packages! 

Clinical trials using ASOs are already underway, and therapies based on ZFP are being worked on. Although there’s plenty of room for optimism, there are some important caveats. First of all, the mice used in these experiments are genetically engineered with an extreme CAG repeat mutation, because they otherwise wouldn’t show symptoms due to their short lifespan. And whether these therapies will translate effectively or safely into humans is another big question mark. For example, although ASOs and ZFPs might be tolerated within the very short lifespan of a mouse, we don’t know the long-term safety or effectiveness in humans. Regardless, we’ll be following every development closely and sharing updates as soon as they are released! 

Summary

• CAG repeats in the HTT gene keep expanding over life, and this somatic instability may contribute to HD’s delayed onset.
• ASO treatments slow repeat expansion by reducing HTT transcription, not just HTT protein levels.
• Multiple experiments, including siRNA, switchable transcription, and Zinc Finger Proteins, confirm that less HTT transcription means less CAG growth.
• Therapies targeting transcription look promising, but it’s still unclear whether slowing somatic instability will change HD onset in humans.

Learn more

Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding

Ever since large genetic studies in Huntington’s disease (HD) revealed that the longer the CAG expansion, the earlier symptoms appear, we’ve known that repeat length matters. Recent work has highlighted just how that repeat length increases within vulnerable brain cells — from about 50 CAGs to over a thousand. 

Understanding how these expansions happen, and how they influence the disease, is crucial for developing the right therapeutic strategies. Can we correct the expanded DNA in affected cells? Well… maybe the cells can do it themselves!

The players in a molecular tug-of-war

DNA-repair genes can strongly influence when HD symptoms begin. For years, researchers have been asking: what do these genes actually do to the faulty stretch of DNA that causes HD? And can we harness this knowledge to delay symptom onset — perhaps long enough that the disease never develops?

A new study in Nature Communications from Petr Cejka’s group reconstructs, molecule by molecule, how two opposing DNA-repair teams compete inside our cells. One team mistakenly lengthens the CAG repeat when trying to fix it, while another trims it back. This elegant biochemical dissection finally shows why players such as MSH3, MLH3, and FAN1 have such a strong impact on disease onset — and opens new routes to slow or even prevent HD.

Why DNA repair matters in HD

DNA is stored in the nucleus forming a double helix, the letters on each strand pair precisely, like the matching teeth of a zipper.

But when the CAG sequence in the huntingtin (HTT) gene becomes too long, the strands no longer line up perfectly. One side can end up with extra “teeth,” creating a mismatch that bulges out from the helix — what scientists call an extrusion loop (imagine a zipper with a kink on one side!).

Everyone inherits some CAG repeats in their HTT gene, but in general, people with 40 or more eventually develop the disease. When these repeats get longer, the DNA can’t zip up neatly anymore, and the cell’s repair machinery rushes in to fix it. And here is where the tug-of-war game starts. Repair can go two ways: some machinery complexes smooth things out and stabilize the DNA, while others accidentally make the repeat longer and longer.

The “expansion crew”: MutSβ and MutLγ

DNA repair usually acts like a spell-checker, scanning for errors, mismatches, or small loops that appear when our DNA is copied. In HD, however, part of the repair team creates the problem.

It’s a literal tug-of-war between two DNA-repair pathways acting on the same repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Two complexes — MutSβ (made of MSH2 + MSH3) and MutLγ (MLH1 + MLH3) — recognize the extrusion loop that forms when there are lots of CAG repeats. Instead of removing the loop, the expansion crew uses the loop as a template and fills in extra CAGs.The result? The repeat grows even longer. MutSβ and MutLγ turn a normal repair job into a “copy-and-paste” mistake that expands the CAG number.

The “contraction crew”: FAN1 to the rescue

Enter FAN1, a nuclease — essentially a pair of molecular scissors — that can do the opposite. FAN1 recognizes these DNA loops and cuts them directly at the site of the problem. Working with helper proteins, the FAN1 crew removes extra repeats instead of adding new ones.

FAN1 also has a clever second trick: it physically blocks MutLγ from partnering with MutSβ, stopping the expansion machinery before it even starts.

A molecular tug-of-war

By setting up both reactions side by side in a test tube, the team revealed a literal tug-of-war between two DNA-repair pathways acting on the same HTT repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Connecting biochemistry to human genetics

The discovery that DNA repair genes affect when symptoms appear didn’t come out of the blue — it started with genome-wide association studies (GWAS) enabled by donated DNA samples from thousands of people with HD. These large-scale studies searched the entire genome for genetic variations that modify the age of onset. The clear message was that genes involved in DNA repair — like MSH3, MLH3, and FAN1 — are major players.

This new biochemical model beautifully explains why those GWAS signals point to repair genes. Variants that boost MutSβ or MutLγ activity (in MSH3 or MLH3) speed up CAG expansion and lead to earlier symptoms, while variants that enhance FAN1 activity can slow expansion and delay onset.

Scientists had long seen these correlations — now, thanks to the Cejka team’s molecular reconstruction, we can finally connect the dots between human genetics and the actual DNA chemistry that could be driving Huntington’s disease.

Why this matters

Understanding these precise mechanisms isn’t just fascinating biology — it’s a roadmap for how we could develop therapies. If we can tilt the balance toward contraction or stabilization, we might slow or even halt the disease process itself.

Some companies are already pursuing this idea:

• ASOs targeting MSH3 or inhibitors of MutSβ aim to reduce expansion activity are being developed by Ionis Pharmaceutical, LoQus23 Therapeutics and Pfizer
• Harness Therapeutics is trying to boost FAN1 function, or mimicking its blocking effect on MutLγ, could offer another route to protect HTT from runaway expansion

What’s next?

Although strong evidence suggests that somatic repeat expansion drives when symptoms begin, this remains a working model. Researchers are now trying to map how these repair processes differ across brain cell types and how they interact within living tissue.

Learning how cells naturally correct their own DNA errors could inspire treatments that let them fix Huntington’s disease from within.

The key challenge is balance: the same DNA-repair systems that sometimes lengthen the HTT repeat also protect the rest of our genome. The ultimate goal will be to fine-tune these pathways to suppress CAG expansion without compromising DNA integrity elsewhere.

If this model holds true, it could open an entirely new therapeutic avenue — targeting DNA repair itself to delay or even prevent Huntington’s disease.

Summary

• HD onset is strongly influenced by genes involved in DNA repair.
• MutSβ (MSH2–MSH3) and MutLγ (MLH1–MLH3) cooperate to nick CAG DNA, adding extra repeats.
• FAN1 and its crew cut the CAG loop instead, removing excess repeats. FAN1 also blocks the MutSβ–MutLγ partnership, preventing expansions.
• These opposing reactions explain why enhancing FAN1 or reducing MLH3/MSH3 activity could delay HD onset.

Learn more

Mechanism of trinucleotide repeat expansion by MutSβ–MutLγ and contraction by FAN1.

On December 4, 2025, uniQure announced they have received the final meeting minutes from their October 29 pre-Biologics License Application (BLA) meeting with the FDA regarding AMT-130. The minutes confirm what was reported in early November: the FDA currently believes the Phase I/II data are unlikely to provide the primary evidence needed to support a BLA submission at this time.

While the most recent press release doesn’t provide new information beyond what we already knew, it does represent an important procedural step. uniQure now has the official written record from the FDA meeting, which will be crucial as they work to chart the path forward.

What Happens Next

UniQure has stated they are carefully evaluating the FDA’s feedback and plan to urgently request a follow-up meeting with the agency in the first quarter of 2026. This meeting will be critical for understanding exactly what additional evidence or analyses the FDA requires.

Matt Kapusta, uniQure’s CEO, emphasized the company’s commitment: “We are committed to collaborating with the FDA to advance AMT-130 to patients and their families as rapidly as possible. The support we have seen these last weeks from the Huntington’s disease community, including patients, families, caregivers, clinicians and advocates reinforces the urgency of the unmet need in Huntington’s disease.”

UniQure has stated they are carefully evaluating the FDA’s feedback and plan to urgently request a follow-up meeting with the agency in the first quarter of 2026.

The Community Responds

The HD community has not remained silent through the whiplash of the FDA’s about-face from just 5 months prior, when they stated that data from the ongoing trials would be sufficient to support accelerated approval. 

In response to this challenging moment, major HD advocacy organizations have come together to issue a Statement of Unity (see More Info section below). Help4HD, HDReach, Huntington’s Disease Society of America, Huntington’s Disease Foundation, and the Huntington’s Disease Youth Organization have pledged to work in partnership to champion the voices of those impacted by HD, particularly when communicating with regulatory bodies like the FDA. This collaboration will focus on broader, shared priorities that affect the many therapeutic approaches currently being developed for HD, ensuring that the lived experiences of families are heard and represented in regulatory discussions.

Multiple Change.org petitions urging the FDA to uphold its accelerated approval pathway for AMT-130 have gathered significant momentum, with tens of thousands of signatures from families, caregivers, and advocates gathered in a matter of weeks – 41,805 at the writing of this article. These petitions and their strong support highlight the urgent unmet need in HD and the devastating impact the regulatory uncertainty has on families who finally saw hope on the horizon.

If you’ve not yet signed these petitions and would like to add your voice, you can find them here:

• Bring Hope to Huntington’s Disease Families: Urge the FDA to Uphold Accelerated Approval
• Accelerate Breakthrough Drug Approval for Huntington’s Disease – uniQure AMT-130

The Data Remain Strong

It’s crucial to remember that nothing about the FDA’s position changes the clinical data themselves. AMT-130 still appears to show a 75% slowing of disease progression compared to matched controls, the strongest evidence we’ve ever seen for a disease-modifying therapy in HD. The treatment continues to show a manageable safety profile with no new drug-related serious adverse events reported since December 2022.

Looking Beyond U.S. Borders

While the U.S. regulatory path has hit an unexpected obstacle, AMT-130 continues to advance in other parts of the world. UniQure has stated they are progressing discussions with regulatory agencies in the European Union and United Kingdom. 

If AMT-130 receives approval in these regions, it would benefit people with HD globally, as clinical data from any regulatory jurisdiction strengthens the evidence base and could ultimately support approval elsewhere.

While the timeline is less certain than we hoped, the goal of bringing an effective disease-modifying therapy to the HD community remains firmly in sight, and it’s clear that the HD community is ready to stand up and fight to make that happen sooner than later.

Why This Matters

The regulatory back-and-forth has been emotionally exhausting for the HD community, and we share in your frustration. However, this is not the end of the road for AMT-130. As we’ve said before, this represents a “save point” in HD drug development, a place where solid evidence exists that we can build upon, learn from, and advance forward. The data showing that HTT-lowering seems to slow disease progression remains a landmark achievement, regardless of regulatory timelines.

UniQure has voiced its commitment to seeing AMT-130 through this process. The company has the official meeting minutes, they’re preparing for urgent follow-up discussions, and they’re exploring multiple regulatory pathways. While the timeline is less certain than we hoped, the goal of bringing an effective disease-modifying therapy to the HD community remains firmly in sight, and it’s clear that the HD community is ready to stand up and fight to make that happen sooner than later.

We’ll continue to follow developments closely and keep the HD community informed as new information emerges.

Summary

• UniQure received official FDA meeting minutes from October 29 meeting, confirming Phase I/II data currently unlikely to support BLA submission
• Company plans to request urgent follow-up meeting with FDA in Q1 2026 to determine path forward
• Major HD advocacy organizations issued Statement of Unity, proposing to coordinate efforts with regulatory agencies
• Community petitions gathered 41,805+ signatures urging FDA to uphold accelerated approval pathway
• Clinical data remain unchanged: AMT-130 appears to slow disease progression by 75% with strong safety profile
• UniQure advancing regulatory discussions in EU and UK as parallel pathways
• This represents a regulatory delay, not the end of AMT-130’s development

More Info

When it comes to thinking about the effects of Huntington’s disease (HD), most people automatically start to think about the brain due to the severe symptoms caused by the breakdown of brain cells. It’s easy to forget that the gene which causes HD is present throughout the whole body – including in the gut! Recent work led by Drs. Carolina Gubert and Anthony Hannan at the University of Melbourne studied how feeding the bacteria in the gut a healthy nutritious meal might improve some signs of HD in mouse models of this disease. Let’s take a closer look at how we can help our bacteria help us.

The tiny tenants living inside of you

A booming metropolis of microbes – tiny organisms too small to see with the naked eye – live in a thriving community in our gut. Microbes can be bacteria, virus, or fungi – things which often have a bad reputation for causing disease. However, most of them are harmless and can actually be beneficial for our health.

Hundreds of types of bacteria call our guts their home and they help to break down complex carbohydrates, produce essential vitamins, and teach our immune system to tell the difference between friendly and harmful bacteria.

Gut bacteria can even talk to our brains! They communicate using chemicals and our nervous system, and the brain talks back! It’s like two friends constantly texting each other. Ever felt stressed or nervous and experienced stomach pain or changes in bowel habits? This is an example of communication through the gut-brain connection. Your brain texts your gut “we’re nervous” and your gut responds with butterflies or nausea.

In this research study, the authors wanted to see if restoring order to the microbiome neighborhood in HD would help gut symptoms, and if a happier gut could improve other HD symptoms associated with the brain through the two-way communication system between the gut and brain.

The population of the microbe metropolis is different in HD

Many people with HD experience gastrointestinal symptoms which decrease their quality of life, including diarrhea, weight loss, incontinence, and constipation. In HD, the gut microbiome – the population of bacteria in the gut – can become imbalanced, meaning that there might be an overgrowth of harmful bacteria and a loss of beneficial bacteria. It’s like a city where all the helpful residents have moved out, and troublemakers have moved in. This in turn can lead to higher stress, less available services and more pollution in the neighborhood.

These changes can also cause a decrease in how many different types and species of bacteria are present in the microbiome, which can also contribute towards the gastrointestinal symptoms patients get in HD. In this research study, the authors wanted to see if restoring order to the microbiome neighborhood in HD would help gut symptoms, and if a happier gut could improve other HD symptoms associated with the brain through the two-way communication system between the gut and brain.

The potential power of prebiotics

So how can we restore a healthy mix of microbes in our gut? The answer is to feed them something that only the beneficial bacteria can eat, helping them to grow in numbers. This food, known as prebiotics, cannot be easily digested by harmful bacteria, allowing the helpful neighbors to once again outnumber the troublemakers.  

The prebiotics used in this study can be classified into two groups: fructooligosaccharide (FOS) and galactooligosaccharide (GOS). FOS is often found in fruits and vegetables, whilst GOS is often found in dairy milk products. A combination of these prebiotics were given to HD mice daily starting from 6 weeks of age and the mice were tested at regular intervals to see if their movement skills, cognitive skills, and gastrointestinal symptoms were improving. Some mice were treated only with water for comparison.

Combating HD through the gut

GI symptoms

First, lets take a look at what happened to the gut. Prebiotic fed mice had softer stools and faster gut transit time, and lower stool output, suggesting that food digestion was smoother. Taking a closer look at how the microbes themselves were impacted, prebiotics seemed to change the diversity of the microbiome, including an increase in beneficial bacteria which aid digestion and immune health.

The more good citizens living in the neighborhood, the more services they can provide! There was also an increase in helpful chemicals produced by beneficial bacteria in prebiotic treated mice. These chemicals, known as short-chain fatty acids, can support both gut and brain health.

Movement symptoms

Next, let’s take a look at movement. Several activities were carried out to test the mice’s performance, including timing how long mice could stay on a rotating rod, how mice move their legs when picked up by their tails, and how they walk on a treadmill. In all these cases, probiotic fed female mice showed better movement characteristics then untreated mice, but there was no obvious improvement in males.

In mouse studies, some aspects of HD do not always manifest the same way in males and females, meaning that treatments don’t always work equally in the two sexes. However, this data is promising as it tells us that improving the health of the gut microbes, sends signals to the brain which can also improve movement symptoms, particularly in females.

Cognitive symptoms

Finally, the scientists investigated if prebiotics improved spatial learning and memory. They used a maze which has three arms the mice can explore. If they continue to explore new arms of the maze, this shows the mice have remembered where they have previously been and are exploring new territory.

Prebiotics improved spatial learning and memory in both control and HD female mice. No improvements were seen in another memory test for male or female mice which investigated how well they remembered objects.

Treatment with prebiotics seemed to improve gastrointestinal, movement, and some memory symptoms in HD mouse models, including better movement coordination in females, improved memory, and healthier gut function.

What does this mean for HD?

The results of this study show that improving overall gut health using prebiotics might have a positive effect on gut symptoms as well as memory and movement symptoms. The results were especially promising in females.

Prebiotics are considered to be very safe treatments, meaning they can be easily incorporated into a clinical trial without huge safety concerns, although mice and humans are very different, so caution is always advised. These encouraging results might also lead to scientists to look at additional ways of improving gut health to see if it might help people with HD.

Summary

• Gastrointestinal issues are a symptom of HD.
• The gut and brain can talk to each other and influence how the other is feeling.
• Prebiotics serve as nourishing food for beneficial bacteria but cannot be eaten by harmful bacteria.
• Treatment with prebiotics seemed to improve gastrointestinal, movement, and some memory symptoms in HD mouse models, including better movement coordination in females, improved memory, and healthier gut function.
• Prebiotics are considered to be very safe and could be easily incorporated into a clinical trial in the future.

Depression and anxiety are common symptoms of Huntington’s disease (HD), and they can make everything harder. New research explores how sertraline, a widely-used antidepressant, affects protein production in HD cells and mice, finding that it prevents motor problems in HD mice and is linked to slower functional decline in people with HD. This study raises an intriguing question: could treating HD with sertraline do more than just improve mood? 

The Depression Factor

Living with HD is challenging enough, but depression and anxiety, two of the most common psychiatric symptoms in HD, can make everything exponentially harder. 

Imagine trying to navigate your daily life while carrying a heavy backpack filled with rocks. Even simple tasks become exhausting, your movements feel more labored, and your brain has less energy for everything else. 

That backpack represents depression and anxiety, and new research on sertraline, a commonly prescribed antidepressant, gives us an opportunity to think about how treating these conditions might lighten the load in meaningful ways.

The Protein Production Problem

The research team, led by scientists at the University of Barcelona, set out to study the molecular effects of sertraline on a specific problem in HD cells: abnormal protein production. Scientists have known for a while that cells in HD produce proteins differently than regular cells. 

Specifically, in some models of HD, some scientists have reported too much activity in a process called translation initiation, which is the initiation of protein production. Think of translation as the cellular assembly line that turns genetic instructions into functional proteins. In some HD models, this assembly line seems to run too fast, like a factory churning out products without proper quality control.

The researchers knew that sertraline can slow down protein production in cancer cells, so they wondered if it could do the same in HD. This study looked at the molecular effects of what sertraline does to protein-making machinery in HD cells and how this affects mice, and potentially people. 

Testing in striatal neurons (the brain cells most affected in HD) from mice that model HD, they found that sertraline appeared to normalize the elevated protein production this team saw. When they treated HD mice with sertraline for four weeks, the mice showed improved learning on motor tasks and coordination compared to untreated HD mice.

From Mice to People

Since the mouse results were promising, the researchers wanted to better understand the effects sertraline might be having in people with HD. So they turned to Enroll-HD, the world’s largest observational study of people with HD, which tracks tens of thousands of people over time. 

They compared people with HD taking sertraline (either alone or with other antidepressants) to people taking other medications or no antidepressants at all. They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time. Specifically, people taking sertraline showed better scores on tests measuring total functional capacity, functional assessment, and independence. 

However, the researchers didn’t see improvements in total motor scores, meaning sertraline doesn’t seem to influence movement symptoms that many people with HD experience. This could be due to the relatively small number of people in some groups or because doses used in mouse studies are much, much higher than the doses doctors prescribe to people.

They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time.

A Cellular Clue

The researchers also made an intriguing discovery about protein production in easily accessible cells. When they looked at skin cells (fibroblasts) from people with HD, they found signs of increased protein production, but only in people whose expanded HTT had fewer than 42 CAG repeats. Treating these cells with sertraline brought protein production back to normal levels.

This cellular finding suggests that the abnormal protein production the researchers are studying may occur in a small subset of people or in select models of HD. Whether this predicts who might benefit most from sertraline’s molecular effects remains an open question. Future research could explore whether measuring protein production in fibroblasts might serve as a biomarker for certain treatments.

Molecular Effects or Mood Effects?

Here’s where interpretation becomes important. This paper primarily focuses on the molecular story of how sertraline affects protein production in HD cells. The research suggests that sertraline can normalize abnormal translation in neurons and in skin cells from some people HD, suggesting the drug may be having a direct effect on cellular machinery that goes awry in HD. This finding is of interest because it could point toward new therapeutic targets.

But it’s equally important to consider sertraline’s primary job: treating depression and anxiety. When depression lifts and anxiety eases, everything becomes more manageable. Your energy improves, your motivation returns, you sleep better, and daily stressors don’t hit as hard. All of these changes can improve how well you function day-to-day, even if the underlying HD pathology hasn’t changed.

Lightening the Load

Consider how depression and anxiety might worsen HD symptoms. If you’re depressed and anxious, stress hormones course through your body, your muscles stay tense, you move less because you lack motivation, and you’re more likely to avoid activities that could maintain your skills. You might struggle more at work, find household tasks overwhelming, or withdraw from social connections that provide support. It can be like trying to function day-to-day while carrying around a 40 pound backpack. 

But what happens if you put that backpack down? Remove the depression and anxiety, and suddenly you’re more likely to stay active, engage with therapies, maintain your job, and participate in activities that keep both your mind and body working well.

The motor symptoms of HD haven’t disappeared, the actual disease progression hasn’t changed, but you’ve removed barriers that were piling onto existing challenges. This doesn’t make the benefits any less real or important, it just means the mechanism might be indirect. Like removing that heavy backpack, treating psychiatric symptoms might make it easier to maintain function and navigate daily life with HD.

Finding Your Right Combination

It’s important to note that sertraline is just one tool in the toolbox for managing HD symptoms. The researchers couldn’t identify clear effects on motor function in the Enroll-HD dataset, which reminds us that no single medication addresses all aspects of this complex disease. Finding the right combination of medications to improve both mood and motor symptoms often takes trial and error for each person.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial. Several medications can help with depression and anxiety, and different medications can address motor symptoms. 

What works beautifully for one person might not work as well for another, so open communication with your medical team about what’s working and what isn’t helps guide adjustments.

What This Means Clinically

This research doesn’t suggest that sertraline is a disease-modifying treatment for HD. What it does suggest is that sertraline may have some effect on abnormal cellular processes in HD, and people taking it appear to maintain function better over time. 

Whether the functional benefits come from correcting molecular abnormalities, from treating depression and anxiety, or from both, the practical implication is the same: addressing psychiatric symptoms in HD matters.

Depression and anxiety in HD aren’t just uncomfortable side effects that people should be expected to tolerate. They’re treatable conditions that, when left unaddressed, can worsen the challenges HD creates. Treating these symptoms is legitimate medical care that could have broader benefits than we might expect.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial.

Talk to Your Doctor

If you or your loved one is living with HD and experiencing symptoms of depression or anxiety, persistent sadness, loss of interest in activities, excessive worry, difficulty sleeping, or changes in appetite, talk to your healthcare provider. 

These symptoms aren’t just uncomfortable; they may actively worsen the functional challenges people with HD are facing. Effective treatments exist, and addressing these symptoms might help more than you think.

Your doctor can help determine whether medications for depression, anxiety, or motor symptoms make sense for you or your loved one, considering your specific situation, other medications being taken, and overall health. Finding the right combination might take some adjustment, but the effort is worthwhile.

The Bottom Line

This research offers molecular insights into how sertraline could affect protein production in HD cells, showing that it could be able to normalize changes in neurons and in cells from some people with HD. The finding that people taking sertraline maintained better function over time is encouraging, whether those benefits come from molecular effects, from treating depression and anxiety, or from both.

The most immediate takeaway is that treating psychiatric symptoms in HD is important medical care, not optional comfort. Whether sertraline proves to have unique disease-modifying properties or simply works exceptionally well at treating depression and anxiety in HD, people who received it maintained better function. That’s meaningful, and it reinforces the value of comprehensive symptom management in HD.

Summary

• Researchers studied how sertraline (an antidepressant) affects abnormally fast protein production in Huntington’s disease (HD) cells 
• Sertraline normalized protein production in HD mouse brain cells and prevented motor coordination problems in mice
• Analysis of the Enroll-HD database showed people taking sertraline maintained better functional capacity (ability to work, manage daily tasks, stay independent) over time, though motor scores didn’t improve
• Sertraline normalized abnormal protein production in skin cells from people with HD with fewer than 42 CAG repeats, suggesting additional work could look at the potential of protein production as a biomarker
• Benefits in people could come from sertraline’s molecular effects on protein production, from treating depression and anxiety (which themselves worsen HD symptoms), or potentially both
• Sertraline is one tool in the toolbox against HD to treat depression and anxiety. Finding the right combination of medications for mood and motor symptoms takes trial and error with your doctor
• Whether sertraline helps by fixing cellular problems or by lifting the “backpack” of depression and anxiety (or both), treating psychiatric symptoms in HD is important medical care that may have broader benefits than expected

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Original research article: “Sertraline treatment prevents motor dysfunction in a Huntington’s disease mouse model and functional decline in patients” (open access).