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

Learn More

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

Welcome back to the HDBuzz monthly research roundup! November was a busy month, with new developments in everything from gene therapy and stem cells to DNA repair, genetic modifiers, and protein folding. Here’s a friendly guide to what scientists learned this month, why it matters, and what it might mean for the future of Huntington’s disease (HD) research and treatment.

uniQure and FDA No Longer in Alignment on Approval Pathway for AMT-130

The most closely watched HD gene therapy program, uniQure’s AMT-130, hit a significant regulatory road bump as uniQure shared a press release stating they are no longer in alignment with the U.S. Food and Drug Administration (FDA). While the company had hoped to use an “external control group” (data from registries such as Enroll-HD) to support their application for approval, the FDA says it won’t accept this approach.

This doesn’t mean the data from the AMT-130 clinical trial shared last month don’t hold true. But it does mean the FDA wants uniQure to use more traditional comparison data before moving forward with a possible approval. Regulatory strategy can change a timeline even when the science looks promising.

This is a reminder that scientific progress and regulatory progress don’t always move at the same speed. Gene therapies for HD, like AMT-130, are still promising, but the path to approval might take longer or require new types of evidence.

SOM3355 moves toward a Phase 3 trial

In more positive news, SOM3355, a drug originally developed for other neurological conditions, received encouraging regulatory signals from both the European Medicines Agency and the U.S. FDA. A Phase 3 clinical trial is now in preparation. SOM3355 is not a disease-modifying therapy; instead, it targets symptoms, potentially addressing movement difficulties, behaviour, or mood.

While the hunt for disease-modifying treatments continues, symptom-focused drugs can make an immediate difference in quality of life for people with HD. If Phase 3 results are positive, SOM3355 could become a valuable new option for treating HD symptoms.

A “tooth fairy” stem-cell therapy enters early clinical testing

A small clinical trial tested a novel approach: infusing people with HD with dental pulp stem cells obtained from human teeth. The treatment was safe, and some participants showed small improvements on clinical measurements. But the study was small, only ran for a relatively short time, and the underlying of the biology of the rationale for how this approach might be working remains uncertain.

It’s an encouraging sign that researchers are exploring bold and diverse ideas, but the HD community should remain cautious. Larger, controlled trials are needed before drawing conclusions about whether this therapy can truly help.

Intermediate CAG repeats behave more like HD than once thought

Scientists took a deep look at “intermediate” CAG repeats; CAG numbers that fall below the traditional disease threshold but above typical “normal” ranges. Using ultra-sensitive methods, they found that even these intermediate alleles can undergo somatic expansion, the same DNA-instability process that drives HD onset and progression.

Surprisingly, this expansion didn’t neatly predict symptoms or disease. People with similar repeat instability differed widely in clinical outcomes. This supports the idea that HD risk exists on a spectrum. CAG length is important, but it’s not destiny, and DNA repair, genetic modifiers, and other biological factors might shift that risk substantially.

Cracking the structure of DNA repair: MutSβ in the spotlight

Repeat expansion in HD is strongly influenced by DNA mismatch repair, the system cells use to fix errors in DNA copying. Researchers have revealed new high-resolution structures of MutSβ, one of the key repair complexes involved in CAG repeat instability.

These structures show how MutSβ recognizes and binds DNA loops (including those formed by repeated CAG sequences), and they hint at why its activity sometimes makes things worse rather than better. Understanding these molecular machines could help scientists design therapies that slow or prevent somatic expansion, potentially delaying onset or slowing progression for people with HD.

A tiny genetic tweak that boosts the cell’s cleanup crew

A newly identified genetic variant may help delay HD onset by ramping up the cell’s recycling and cleanup pathways, especially autophagy, the system cells use to remove damaged proteins and waste. This is part of a growing wave of research showing that genetic modifiers (genes other than HTT) can accelerate or delay symptoms.

Modifiers are rewriting the story of HD. Even people with the same CAG repeat length can show dramatically different ages of onset. Understanding these modifiers might someday help researchers design treatments that mimic their protective effects.

Untangling protein folding in HD

Expanded huntingtin protein can misfold and forms harmful aggregates, but the details of this process have been notoriously hard to nail down. New structural biology tools are giving researchers a clearer look at how the expanded protein folds incorrectly, and how that misfolding leads to toxicity.

The metaphor in the article’s title captures it well: imagine trying to fold a shirt that suddenly has sleeves three times longer than expected. Better understanding of misfolding opens the door to new strategies, molecules that stabilize huntingtin, prevent aggregation, or help cells clear misfolded proteins more efficiently.

What we learned this month

Across November’s articles, several themes emerge:

1. Risk and progression are nuanced

Intermediate CAG alleles and genetic modifiers show that HD is perhaps more complex than a single genetic change.

2. DNA repair remains a key driver of HD biology

Multiple studies point to somatic repeat expansion as a central player, a target for future therapies.

3. Discovery science is thriving

From high-resolution protein structures of genetic variants, basic research continues to uncover the molecular foundations of HD.

4. Clinical innovation is broadening

Gene therapy, small molecules, and even stem-cell approaches are all being explored, each with its own challenges and opportunities.

5. Regulator–industry alignment matters

The AMT-130 story shows that even promising science can hit speed bumps. Patience and persistence are part of progress.

Looking ahead

As 2025 winds down, HD research is more active, more interdisciplinary, and more globally connected than ever. Whether it’s genetic modifiers, new drug targets, or next-generation clinical trials, momentum is building on many fronts simultaneously.

Stay tuned for the HDBuzz end-of-year review, where we’ll recap the most important HD research stories of 2025, and look forward to what’s coming next.

Imagine a busy clothing factory. Proteins are like newly sewn shirts coming off the machines. They’re floppy, wrinkled, and can create a giant mess if they’re left unfolded. Normally, the cellular clothing factory employs “chaperone proteins” that act like skilled pressers. They grab each shirt, apply energy from a hot iron, and carefully fold it into the right shape so everything stays neat and tidy. 

But Huntington’s disease (HD) creates abnormally shaped clothes that can throw the chaperone folders off. When that happens, proteins, like irregular shirts, tend to be folded incorrectly, get tangled up, and create a huge mess. In new work published in Nature Communications, a team of researchers dove into how they could improve the protein folding process in HD by engineering extra chaperone folders. So what did they find, and what does this mean for HD?

Folding a shirt with 12-foot arms

HD is caused by an expanded stretch of genetic letters in the huntingtin gene that produce an extra-long protein, called expanded huntingtin. That extra-long protein creates harmful clumps that form inside cells. If the cell is a busy clothing factory, expanded huntingtin is like a shirt with 12 foot arms – hard to fold and store properly, causing a big mess.

Usually, there are helper proteins, called “chaperones,” that work throughout the cell to make sure other proteins fold correctly and prevent them from clumping. However, in diseases like HD, this chaperone system can become overwhelmed. There’s just too much expanded huntingtin for them to keep up with.

If the cell is a busy clothing factory, expanded huntingtin is like a shirt with 12 foot arms – hard to fold and store properly, causing a big mess.

PEX19: solo folding machine

Chaperones need a constant supply of energy in the form of a molecule called ATP, and a team of other helper proteins, to do their job correctly. Since they depend on this support system, it makes chaperones complicated to turn into medicines – they require too much energy and teamwork. It’s like trying to use a whole factory instead of just one machine to do a job. This study focuses on a specific type of chaperone called PEX19, which is unique because it works without the need of energy (ATP) or any helper protein. 

PEX19 normally helps certain proteins get to a part of the cell called the peroxisome. Peroxisomes are little recycling and detox factories inside your cells, working to break down waste and harmful substances, such as fats and poisons, to keep the cell healthy by converting them into harmless water and oxygen. Because PEX19 works by itself and does not require ATP, it could potentially be harnessed to address protein clump formation without the need to engineer a treatment that incorporates partner proteins. 

Clearing clumps in multiple models of HD

The main goal of this research was to find a way to prevent the clumping of the expanded mutant huntingtin protein that contributes to the onset of HD symptoms. The researchers thought that, given its unique characteristics, they could modify PEX19 at the molecular level to target and remove harmful huntingtin clumps. To this end, they produced different modified versions of the PEX19 chaperone and tested which version prevented the formation of protein clumps in different organisms that model HD.

First, they engineered tiny little yeast cells that produce the huntingtin protein. If left untreated, protein clumps form that make the yeast sick. The researchers added to the yeast cells two specially designed versions of PEX19, and observed that this treatment stopped huntingtin clumps from making the yeast sick. 

Next, they added these two versions of PEX19 to human HD cells grown in a lab dish, and observed that huntingtin protein clumps formed much more slowly. Finally, they treated HD fruit flies with their most effective version of PEX19 and observed that these sick flies lived longer and could climb better, a skill that deteriorates in flies with the gene for HD. They think this was because the sticky clumps in their brains were reduced.

The team observed that man-made variations of PEX19 can prevent the initial formation of protein clumps, but they cannot break apart clumps that had already formed, because this requires significant energy.  

Stopping the mess before it starts

These interesting observations suggest that an energy-independent chaperone, PEX19, can be engineered to target and prevent the formation of huntingtin protein clumps in yeast, human cells, and fruit fly brains. This suggests that the two special versions of PEX19 may have therapeutic potential against HD in humans. 

In addition to these takeaways, the researchers identified the specific mechanism by which these two PEX19 versions inhibit protein clumps, an insight that is crucial for the development of drugs that mimic the actions of PEX19. The team observed that man-made variations of PEX19 can prevent the initial formation of protein clumps, but they cannot break apart clumps that had already formed, because this requires significant energy.  

It’s the difference between neatly folding each unwieldy, floppy-sleeved shirt right after it’s sewn, versus tackling a huge, messy mountain of them. Although this is a limitation of engineered PEX19, the fact that the chaperone is energy-independent and does not require many helper proteins still makes it an attractive candidate for therapeutic development.

Tweaking the folds for a better fit

This research makes a significant contribution by introducing a novel strategy for developing therapies for Huntington’s disease and potentially other protein aggregation disorders. It demonstrates the feasibility of engineering an ATP-independent chaperone to target and reduce the clumping of a disease-causing protein. This approach offers an alternative to traditional chaperones that rely on complex cellular machinery and energy, which can limit their effectiveness in diseased cells.

Future work should focus on further optimizing the engineered PEX19 variants to enhance their specificity and potency by fine-tuning PEX19 architecture to bind better to the huntingtin protein. Additionally, testing these variants in more complex mammalian models and eventually in clinical trials would be crucial for their development as a therapeutic agent for Huntington’s disease.

Summary

• The clumping of an expanded huntingtin protein inside cells contributes to Huntington’s disease (HD). 
• Traditional protein chaperones that could prevent formation of protein clumps require significant energy (ATP) and helper proteins, making them unsuitable as simple treatments.
• This study analyzed many different versions of PEX19, a unique chaperone that functions independently and does not use ATP, for their ability to inhibit the formation of huntingtin protein clumps in human and animal cells. 
• The research team identified two engineered versions of PEX19 capable of preventing huntingtin protein clumps in yeast, human cells, and fruit flies.
• The engineered PEX19 variants can prevent new clumps but are unable to break down existing ones. 
• The results offer a simplified approach for potential HD therapies and may inspire future research into optimizing these variants and testing them in mammalian models and clinical trials.

Learn MoreOriginal research article, “Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin” (open access).