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This month’s Huntington’s disease (HD) research roundup spans work from the dinner table to DNA repair. Scientists explored whether eating on a schedule could help clear toxic proteins, uncovered early signs of muscle loss in HD, and examined how childhood experiences shape adult mental health. Other teams investigated the gut–brain connection, identified new protein biomarkers, mapped toxic huntingtin clumps, and revealed how tiny changes in DNA repair genes might speed up disease onset. Together, these discoveries highlight both the complexity of HD and the many creative ways researchers are working to tackle it.

Appetite for Answers: Does Eating on a Schedule Help with Huntington’s Disease?

This month we covered work from researchers who are eyeing whether when (rather than what) you eat could benefit people with HD. Known as time‑restricted eating (TRE), the idea is to limit meals to a daily window, like 12 p.m. to 8 p.m., and let the body fast the rest of the time. In animals that model HD, this eating pattern appears to kick-start a cleanup process inside cells (called autophagy) that may help clear out harmful huntingtin protein clumps from the brain.

But before giving your fridge a curfew, remember this: these promising results are from animal studies, not people. And many folks with HD already struggle with unintended weight loss, problems with choking, and muscle wasting, so fasting could unintentionally make symptoms of the disease worse. So even though more research is needed before TRE is prescribed for HD, we know that a healthy diet filled with nutritious food has clear health benefits for everyone.

Body in Decline: Muscle Loss as an Early Symptom of Huntington’s Disease

A new study shows that HD doesn’t just impact the brain, it quietly reshapes the body too. In the earliest stages, people with HD already appear to have signs of reduced muscle mass (60%) and weaker grip strength (45%), even when walking still felt normal. On top of that, over half (55%) seemed to be at risk for or already experiencing malnutrition, a worrying early red flag.

These early physical declines aren’t just numbers, they’re affecting daily life. Reduced strength and nutrition were linked to worse motor symptoms, increased dependence on others, and trouble planning or organizing tasks. The good news is that there’s hope with practical solutions that can be implemented today. Nutritional support, high-calorie or easy-to-eat meals, and staying active with exercises like walking or resistance training could help towards preserving muscle, brain health, and independence. Looking ahead, measuring changes in body composition may one day offer a simple, non-invasive way to monitor disease progression.

Carried from Childhood: Childhood Experiences and Adult Mental Health in Families with Huntington’s Disease

Some childhood memories stick with us in surprising ways, even long into adulthood. A study from Italy looked at adults who grew up with a parent affected by HD and discovered that it wasn’t major crises, but ongoing emotional turbulence, like constant criticism, unpredictable moods, or feeling unsafe speaking up, that had the strongest impact on adult mental health.

Those who grew up in HD families were more likely to struggle with low mood, anxiety, and feeling overwhelmed, even when major traumatic events hadn’t happened. The research helps name what many people have quietly carried for years and why emotional support matters just as much as practical help. Most importantly, it reminds us that healing is possible, and you don’t have to carry it alone. 

If you would like to learn more about support systems and resources available for young people impacted by HD, we encourage you to reach out to the Huntington’s Disease Youth Organization (HDYO) or the Huntington’s Disease Society of America (HDSA) National Youth Alliance (NYA). You are not alone, and support is available. 

The Gut–Brain Superhighway in Huntington’s Disease: Clues From the Microbes Inside Us

Our gut and brain are always chatting – think of it like a busy two-way highway where nerves, immune signals, and gut microbes all send messages back and forth. In HD, this roadway gets bumpy: gut and brain barriers become leaky, inflammation kicks in, and the usual balance of gut microbes gets thrown off, like traffic patterns suddenly going haywire.

Researchers are looking into how we might ease the congestion. Lifestyle factors like exercise or a stimulating environment have helped gut health in animal models, and certain antibiotics showed less inflammation and better nerve cell protection in lab studies. While broad spectrum antibiotics aren’t a realistic option for intervening with the HD microbiome long term, these studies help identify molecular players that could be targeted with new medicines down the road to improve gut and, potentially, brain health in HD. 

City Under the Microscope: How Two Proteins Could Help Track Huntington’s Disease

Scientists are on the hunt for better ways to measure HD progression, even before symptoms show. In recent work, two proteins, CAP1 and CAPZB, identified using a blood test, have become lead candidates . In a study from Cyprus, researchers scanned the entire blood protein landscape and discovered that CAP1 levels dip in people in the very earliest stage of HD, while CAPZB levels rise consistently throughout the disease.

This month’s Huntington’s disease (HD) research roundup spans work from the dinner table to DNA repair. Together, these discoveries highlight both the complexity of HD and the many creative ways researchers are working to tackle it.

This is important research because we need more biomarkers that track with HD progression. Right now, neurofilament light (NfL), the leading HD biomarker, only tells part of the story. But having others like CAP1 and CAPZB joining the team would give researchers more ways to track disease progress and test treatments earlier and more accurately. If future studies in larger, more diverse groups confirm these findings, one day a simple blood test could reveal whether a new treatment is slowing HD before noticeable symptoms take hold, an exciting possibility for an early intervention.

Cracking the Protein Puzzle in HD: New Blueprints Offer Hope for Stopping Damage Early

Researchers have advanced what we know by mapping the structure of the huntingtin protein fragments, piece by piece, using ultra-precise imaging. Sticky protein clumps, called exon 1 fibrils, are the misfolded proteins that accumulate in HD and participate in the havoc that is wreaked in brain cells. Scientists discovered that these toxic clumps have a tight, dense core wrapped in a loose, fuzzy coat. With this new work, we can see exactly how each part fits together.

In a clever follow-up, researchers added a tiny amount of curcumin, the active ingredient in turmeric, to the mix in lab dishes. This gentle tweak seemed to reshape the protein clumps into forms that were slower to assemble, less sticky, and less harmful to neurons. The studies offer a new kind of blueprint as a way not just to clean up damage after it happens, but potentially to build safer versions from the start. 

But don’t start downing massive amounts of curcumin or turmeric with the hopes of altering the expanded huntingtin structure. These findings are early-stage and in a lab setting only and more work is needed to better understand the effects in people. However, they give scientists an exciting map to start designing treatments that target the blueprint of the huntingtin protein.

When DNA Repair Goes Off-Script: How a Small Change in FAN1 Can Accelerate Huntington’s Disease

Deep inside our cells, proteins work like stagehands keeping DNA maintenance running smoothly. But researchers have spotlighted a tiny change, called the R507H mutation, in one of the DNA repair proteins, FAN1, that causes it to trip up its performance. This small slip weakens FAN1’s grip on PCNA, a partner protein that helps it stay on track during DNA repair, ultimately letting harmful DNA loops accumulate in the huntingtin gene, seemingly speeding up disease onset.

This work is important because it helps explain why two people with identical CAG repeat numbers within their huntingtin gene might start showing symptoms at very different times. Understanding the R507H change in FAN1 gives researchers a new target. If they can restore FAN1’s grip or stabilize its teamwork with PCNA, they may be able to slow the progression of HD. This opens up a fresh strategy in the hunt for therapies by targeting genes that modify the onset of HD.

Two research teams have uncovered how a small change in FAN1, a DNA repair protein, can speed up Huntington’s disease (HD). In back-to-back papers in Nature Communications, they show how a single mutation known to influence when symptoms begin appears to prevent FAN1 from working properly. This seems to make it harder for cells to keep harmful DNA changes in check. Let’s look at what they found.

DNA Repair and Repeat Expansions in HD

Keeping our genetic material in check is a constant job for the cells of our body. Our DNA is under constant stress from all kinds of damage, ranging from UV damage caused by the sun to correcting molecular errors to ensure new mutations aren’t made, and cells rely on a network of repair proteins to fix problems before they cause harm.

The role of these DNA repair players has been shown to be important in HD. In particular, many different teams of researchers have shown that the C-A-G DNA letter repeat region of the HTT gene can get longer and longer over time in some types of cells. This so-called somatic instability, or somatic expansion, is thought to play a central role in how early and how severely the disease appears.

FAN1 is one of several proteins that help manage these repetitive DNA sequences, typically preventing them from expanding over time. Another key player in this repair process is PCNA, a protein that acts like a supporting actor, helping the leading players, including proteins like FAN1, stay on script during DNA repair.

The R507H Mutation in FAN1

Generally, the longer the CAG number someone has, the earlier they will begin to experience symptoms of HD. However, we also know that for two people with the exact same CAG number, their symptoms may begin decades apart. This is in part due to things called genetic modifiers: other DNA changes in the genome, aside from the HD mutation, which are associated with differences in when symptoms begin.

Some people with HD carry a specific change in the FAN1 protein, known as the R507H mutation. While this might seem like a confusing code, the letters and numbers let researchers know precisely where and what the change is, like the page and line numbers in a script – at the 507th spot within FAN1, an “R” protein building block is swapped for an “H”.

This single-letter change alters just one building block in a protein of more than 1,000 building block letters, or amino acids. Although it’s a small change, people carrying this FAN1 variant tend to develop symptoms much earlier than expected based solely on their CAG number. Until now, the reason behind this link wasn’t well understood.

Using powerful microscopes, researchers were able to visualize how FAN1 normally binds to PCNA. This binding allows FAN1 to position itself properly onto DNA to carry out its repair work. But the R507H mutation weakens this interaction, reducing FAN1’s ability to hold on to PCNA and stay in place during repair.

A Closer Look at the Consequences

Both studies examined the effects of the R507H mutation in detail. One found that FAN1’s ability to cut the loops that form in CAG repeats in DNA seemed to be reduced. The other suggested that the entire FAN1–PCNA–DNA complex was less stable and less effective at DNA repair when the R507H mutation was present.

These DNA loops are also called extrusions, as they stick out awkwardly from the DNA helix, like a stage prop out of place. These extrusions tend to form in regions with many repeats, like the CAG tract in the huntingtin gene. The longer they are, the more unwieldy they become. If not properly repaired, they can lead to further expansions, making HD symptoms worse over time.

Why This Matters

These findings offer an explanation as to why the R507H mutation might be linked to earlier HD onset: the mutation disrupts FAN1’s repair activity, which can lead to faster accumulation of harmful DNA changes, and more somatic expansion. Overall, this could explain why this genetic modifier hastens the onset of HD symptoms.

These detailed insights into how FAN1 can go off script in some people with HD not only deepen our understanding of the disease, but also open up new directions for treatment. By mapping out the exact role of FAN1 in HD pathology, researchers can begin to explore ways to restore proper repair function, for example, by designing therapeutics that stabilize the FAN1–PCNA interaction or by boosting FAN1 levels.

And there are companies already doing exactly that! For example, Harness Therapeutics is working on developing specialized DNA molecules, known as antisense oligonucleotides or ASOs, that are designed to boost production of FAN1, with the overall aim of making the C-A-G repeat shorter.

While much of HD therapeutic research has focused on lowering levels of the harmful huntingtin protein, these results suggest that strengthening the cell’s natural DNA repair processes could offer another way to slow disease progression. Perhaps this could one day be applied together with huntingtin lowering. The more approaches we explore, the greater the chances of finding an effective therapy for HD.

Finally, recognizing this mutation in people with HD may help tailor care strategies in the future, pointing toward a time when therapies are prescribed based on each person’s genetic makeup.

Moving Forward

Thanks to these two new studies, we now have a clearer picture of how a small change in FAN1 can tip the balance, accelerating the progression of HD. This insight was only possible because of the generosity of HD families around the world who contributed samples to the large genetic studies that first identified this variant.

With more research, we may one day be able to correct or compensate for that shift, helping people with HD live healthier, longer lives.

Summary

• FAN1 is one of several DNA repair proteins that help keep repetitive DNA sequences in check.
• A specific change in FAN1, called R507H, seems to reduce its ability to interact with PCNA, another key repair protein.
• This disruption appears to make it harder for cells to manage CAG repeats in the huntingtin gene, potentially accelerating HD onset.
• Understanding this process opens the door to new therapeutic strategies, such as stabilizing DNA repair pathways.
• These insights were made possible thanks to HD families worldwide, whose contributions to genetic studies enabled the discovery of this mutation.

Learn more:

“A FAN1 point mutation associated with accelerated Huntington’s disease progression alters its PCNA-mediated assembly on DNA” (open access).

“Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair” (open access).

Two studies from the same research group have helped to provide some important blueprints for Huntington’s disease (HD) research, helping us to more clearly understand what the toxic fragment form of the expanded huntingtin protein is doing. The first study maps the structure of the toxic fragment protein, called exon 1, that clumps together to form fibres. The second study shows how a natural compound could change the shape of these protein fibres, potentially making them less harmful to brain cells. Let’s get into it. 

Understanding the Huntingtin Protein, Atom by Atom

Imagine trying to build a machine with a collection of parts but no instructions about how they go together. Some pieces look familiar, others are oddly shaped, and a few keep jamming the gears. 

That’s what scientists studying HD have been facing for decades. We know that in HD, an expanded form of the huntingtin protein is made, and that this seems to misfold and clump into damaging shapes and structures. We had some early snapshots of what these clumps might looks like. but, until very recently, we haven’t had a clear “blueprint” to show what those shapes look like, so it’s tricky to figure out exactly how they might be toxic.

Two studies have used cutting-edge microscopes and other technologies to delve into exactly what these toxic huntingtin exon 1 protein clumps look like at the atomic level. This means understanding where every atom of the protein is in 3D space, and how they are all connected – a ton of really cool detail. So what did they find? 

Finding the Right Fit: Mapping Protein Clumps

In the first study, published in Nature Communications, scientists set out to solve one of the big structural mysteries in HD: what do huntingtin exon 1 fibrils actually look like at the atomic level?

These fibrils are dense, fibre-like structures made of fragments of the huntingtin protein, called exon 1, that stack together to form big assemblies. They form inside brain cells when the huntingtin protein is abnormally expanded in HD. These protein assemblies, also called aggregates, are believed to be key contributors to cell damage in HD.

Until now, researchers were working without clear assembly instructions about these fibres. While similar types of protein clumps in other brain diseases like Alzheimer’s and Parkinson’s have been structurally mapped, HD fibrils remained largely uncharted territory.

Using a combination of advanced methods such as cryo-electron microscopy, nuclear magnetic resonance spectroscopy, and molecular dynamics (what a mouthful!), the team created a detailed model of these exon 1 fibrils. It’s like taking a blurry photo of a complex machine and finally replacing it with a 3D CAD model so that every detail of it’s mechanics is clearly mapped out.

What they found was not just a tightly packed core, but also a more flexible, fuzzy outer layer. This “fuzzy coat” may play a role in how the fibrils interact with other molecules in the cell and how they trigger different responses.

Another clever technique used in the study allowed the researchers to see how well the protein fibres can “breathe”. This helped identify which parts of the fibrils are buried deep in the fibre core and those that are more exposed on the surface. 

The model built by the researchers provides critical insight for other scientists to design tools to detect or break apart these clumps in the future, as well as to continue to study how these fibres contribute to the signs and symptoms of HD.

Can We Change the Design Mid-Build?

The second study, also published in Nature Communications, took this one step further. With the blueprint in hand, they asked: can we tweak how these structures form in the first place?

The team explored this idea using curcumin, a naturally occurring polyphenol compound found in turmeric. While curcumin itself is not a drug, it’s long been studied for its anti-inflammatory properties, which are thought to be linked to how it interacts with proteins. But don’t start downing massive amounts of curcumin or turmeric with the hopes of altering the expanded huntingtin structure. These studies were only done in a test tube and cells grown in a dish, so lots more work is needed before we know if there would be beneficial effects in people.

In a test tube, the researchers added very small amounts of curcumin to mixtures of huntingtin exon 1. Think of it like adding a part from the assembly line earlier on in the build to see if the final product turns out better. That small change had ripple effects on how the huntingtin fibres formed. The fibrils assembled more slowly, and the resulting shapes appeared to be different; less rigid and “sticky,” but encouragingly they seemed to be less stressful for cells.

The team also showed that the curcumin-influenced fibrils seemed to be structurally distinct. When they advanced to testing the effects of curcumin on cells in a dish, these altered fibres didn’t appear to trigger the same level of stress response in neurons in a dish.

A key difference seemed to be in how the folding pattern of the fibres was altered. These fibres had a slightly different blueprint, made from the same pieces that seemed to be less harmful in cell models. 

What This Means for the HD Community

Together, these studies help reveal how the pieces of the HD puzzle fit together, and suggest new ways that we might target or stabilize fibrils to protect brain health. Understanding the shape of these harmful protein aggregates gives scientists a map to work from, to better understand how downstream damage might occur. 

Even more exciting, the second study shows that it could be possible to shift how these aggregates form, potentially impacting how they behave. Instead of trying to clean up a mess after it’s formed, we might be able to build a different structure from the start, one that doesn’t cause harm.

It’s important to note though that curcumin is not a treatment. We certainly don’t have sufficient evidence to suggest that people with the gene for HD or with HD should start taking curcumin or turmeric as a means of altering the expanded huntingtin protein shape. 

Additionally, these are lab-based studies done in test tubes and on cells grown in a dish, not in animal models or in clinical trials. But the principle is promising as a jumping off point for other studies. If researchers can find small molecules that guide huntingtin into safer shapes, they may be able to stop or slow the disease process one day.

Assembling the Future

The story of HD is, in many ways, a story of an assembly line gone wrong; a single genetic glitch creates a cascade where alternative parts are used inside brain cells. These two studies help us understand that story more clearly, offering detailed diagrams of how the pieces fit and the hopeful possibility of redesigning the system altogether.

Science is often like working a massive, 10,000-piece puzzle without the box so that we can see the final picture. But every time we snap a few pieces into place, the bigger picture becomes easier to see. With each structural insight, each smart intervention, we move closer to building a future where HD is a solvable problem, and not an unsolvable puzzle.

Summary

• HD is caused by an expanded huntingtin protein that clumps into harmful fibres.
• Two new Nature Communications studies reveal:
  • A detailed atomic map of huntingtin exon 1 fibres.
  • Evidence that a natural compound, curcumin, can alter how these fibres assemble, making them less toxic.
• These findings provide blueprints for designing potential new strategies to stop HD damage earlier.
• However, without support from more established studies, people shouldn’t take curcumin or turmeric as a means of altering expanded huntingtin.

Learn more

Atomic structure of huntingtin exon 1 fibrils reveals a compact amyloid core and dynamic fuzzy coat (Open Access) 

Curcumin reshapes huntingtin exon 1 fibrils into less toxic conformers (Open Access)

Biomarkers are measurable signs of what’s happening inside the body and are essential for running successful Huntington’s disease (HD) trials. Right now, neurofilament light (NfL) is the star of the HD biomarker world, but we need more players on the team. A new study from Cyprus scanned every type and amount of protein molecules found in blood samples, to see how these changed over time in people with HD. They found two potential biomarker candidates, CAP1 and CAPZB, which seem to be linked to very early changes in HD. With follow up studies, these findings could add powerful new tools for tracking disease progression and measuring the impact of future treatments.

Biomarkers Are Critical For HD Research

Imagine running a race without a finish line. That’s what testing an HD treatment would be like without biomarkers. You could hand someone a promising new drug, but without a way to measure what’s happening in the brain, you wouldn’t know if it’s helping, hurting, or doing nothing at all.

That’s why biomarkers are so important. In HD, one of the best so far is neurofilament light (NfL), a protein released when neurons are damaged. NfL seems to be reliable, it’s being used in many ongoing trials, seems to track with some of the earliest changes that HD causes, and it’s taught us a lot about how possible HD treatments might impact brain health. But no single biomarker can capture the whole progressive story of HD, or how things might change with different treatments. We need a team of biomarkers that can cover different angles, especially ones that show up before the earliest of symptoms start.

Enter this new research study, which is a wide-angle look at the blood for signs of HD, even in its earliest days.

So, What’s A Proteome, Anyway?

Think of your body as a giant city. Your genes are the blueprints for all the buildings, roads, and systems. Proteins are the workers – the electricians, the bus drivers, the teachers, the police officers. They’re the ones making things actually happen.

The proteome is the full roster of those workers at any given moment. And just like in a real city, the lineup changes depending on what’s going on, like if there’s a festival, a storm, or a traffic jam, the people you would want on your crew would change. Proteomics is the science of counting and studying all those workers to see who’s showing up, who’s missing, and who’s acting differently than usual.

In this study, the “city” in question was the blood of people with and without HD.

The Study Breakdown

The researchers studied 36 people with the gene for HD, split into three groups:

• Asymptomatic: gene-positive but no clinical signs yet
• Early symptomatic: subtle movement or thinking changes
• Advanced symptomatic: more pronounced symptoms affecting daily life

They also included 36 healthy controls, all from Cyprus. Using blood serum (the clear liquid part of blood), they analyzed thousands of proteins to see which ones changed at each stage of HD.

The advantage of blood serum is that it’s far easier to collect than spinal fluid, no lumbar punctures required, making it a practical (and much desired!) source for future biomarker testing.

Early Trouble In The Cell’s Skeleton

The first finding from this research seemed to show up before symptoms appeared, suggesting there may be changes in proteins linked to the cell’s cytoskeleton. The cytoskeleton is the internal scaffolding that gives cells their shape and allows them to move and connect.

This work suggests the city’s buildings may be losing their supporting beams before any cracks appear in the walls. Identifying changes that happen early in HD, before symptoms are readily apparent, will help researchers identify key molecular events in HD progression.

As the disease advanced, two other themes emerged. First, the complement system, a frontline part of the immune response, seemed to be stuck in an overactive state, which in the brain could mean inflammation and loss of brain cell connections. Second, lipid and cholesterol regulation appeared to go off balance, which matters because cholesterol is vital for healthy brain cell communication.

While all of these are interesting findings, none of this is particularly new for HD researchers. There have been several studies looking at cytoskeleton differences in brain cells, changes to the complement system, and cholesterol dysregulation in HD before. But those studies have largely focused on the molecular changes HD causes within those biological functions, and not using those changes to identify biomarkers.

Biomarkers are measurable signs of what’s happening inside the body and are essential for running successful Huntington’s disease (HD) trials. Right now, neurofilament light (NfL) is the star of the HD biomarker world, but we need more players on the team.

Meet CAP1 And CAPZB

From the long list of changing proteins identified in this study, two stood out for the researchers:

• CAP1 seemed to be lower in people with HD, especially in the asymptomatic group. This made it stand out to the scientists as a strong candidate for an early-warning biomarker, one that changes before symptoms. CAP1’s role in the cell is to help keep the cytoskeleton stable.
• CAPZB seemed to be higher in all HD stages, piquing interest as a potential general disease marker that could be useful for tracking HD once it’s underway. CAPZB also works on the cytoskeleton, specifically regulating actin, a key structural protein.

The More the Merrier

If validated in larger, more diverse groups, CAP1 and CAPZB could join NfL in the HD biomarker toolkit. Together, they could help flag HD-related changes years before symptoms start, which will be critical for advancing trials aimed at treating HD before the more obvious symptoms of the disease begin. They could help track how fast the disease is progressing, which could help people with planning life events. And they could help show whether a treatment is making a difference, which is why biomarkers are so critical for HD research.

This is especially important in prevention trials, where the goal is to treat people before the disease has visibly started. Without early biomarkers, we’d have no way to see if those treatments are working.

Some Things To Keep In Mind

This study was done on a very specific population of people – those from the small island of Cyprus. Because this is a limited population of people, there could be “founder effects” at play, which means that the population of people with HD on Cyprus could have started from one person or just a few individuals that, over time, produced the family(ies) on Cyprus with HD. 

In theory, that limited initial person/people could have had unique genetic signatures that made the biomarkers identified in this study specific for them and their progeny. Because of that, a more diverse set of people needs to be studied before we could say if these are solid biomarkers to chase for HD. 

Another thing to keep in mind here is that only 36 people were assessed in this study. That’s a small number of people when it comes to a biological study. Combined with the fact that the diversity is limited, and that small pool of participants could really mask results or skew findings.

Even Still, These Types of Studies Are Critical

While the points above are important caveats that suggest we should interpret these findings with a healthy pinch of salt until larger studies are done, the importance of these types of studies for advancing HD research cannot be overstated. 

Having biomarkers that track with disease progression, particularly in people that are at the earliest stages of HD, is essential for advancing disease modifying drugs. This is especially important as we move toward trials aimed at treating people with HD earlier on in their HD journey, perhaps even before notable symptoms arise. 

Another important note from this work is that it was done using blood serum, showing that researchers are committed to discovering biomarkers that track with early disease progression that can be measured in a minimally invasive way. We know everyone would appreciate not having to get a spinal tap at every appointment! So while we’re not quite there yet, it is certainly something scientists are working toward.

Lastly, the results from this study were made possible by “omics” studies – giant, detailed inventories of all the parts in a living thing, whether that’s all the genes, all the proteins, all the fats, or all the other molecules that keep it alive. These types of research studies that look at how everything changes, then narrow in on those things that change the most have transformed our understanding of HD over the past decade. It was omics studies that initially defined genetic modifiers from the GeM-HD Consortium study, contributing to the discovery of somatic instability. And omics studies will undoubtedly help usher in the forthcoming treatments we’re all eagerly awaiting.

Having biomarkers that track with disease progression, particularly in people that are at the earliest stages of HD, is essential for advancing disease modifying drugs. This is especially important as we move toward trials aimed at treating people with HD earlier on in their HD journey, perhaps even before notable symptoms arise. 

The Road Ahead

First and foremost, before CAP1 and CAPZB can move from research to clinic, it’s critical that scientists test them in bigger, global HD cohorts. They also need to follow people over time to see how levels might shift as HD progresses in those larger populations. They should also check whether they’re unique to HD or also change in other brain diseases.

So, while there’s a long road ahead for CAP1 and CAPZB, work advancing new biomarkers for HD is critical, and it’s ongoing. It’s especially important as we move toward clinical trials aimed at treating HD earlier, perhaps even before symptoms arise. And the added benefit of blood biomarkers is incredibly exciting. Imagine having a simple blood test that could tell researchers, with confidence, that a new drug is slowing HD in its tracks. That’s the kind of advancements that these biomarker studies could bring. 

Summary

• Biomarkers are crucial in HD research for measuring treatment effects.
• NfL is a strong HD biomarker, but more are needed for a complete picture.
• This study scanned the blood proteome of people with and without the gene for HD from the small island of Cyprus.
• Two proteins seemed to stand out: CAP1 (lower in people with early HD) and CAPZB (higher across all stages of HD), both linked to early cell structure problems.
• If validated in larger more diverse populations of people, they could help detect and track HD years before symptoms, a critical advancement for future clinical trials aimed at treating HD earlier, perhaps even before symptoms arise.

Learn More

Original research article, “Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression” (open access).

While Huntington’s disease (HD) primarily affects the brain, the genetic change that causes the disease is present in every cell throughout the body. Because of that, it has influences beyond the brain, including in the gut. Increasing evidence suggests that changes in gut microbes, leaky barriers, inflammation, and nerve signaling may contribute to HD progression. A recent review of published research maps the “gut–brain superhighway” in HD, highlighting where traffic flows smoothly, where it’s blocked, and where detours might offer new treatment options.

How Human Are You, Really?

If someone were to ask you what species you see when you look in the mirror, you would undoubtedly say human. But people are actually made up of more microbes than anything else. Shockingly, there are more microbial cells in your body than human cells. And 99% of the genetic material in your body is from microbes – only 1% of your DNA is of human origin! So it makes sense that when we think about human biology, we should seriously consider the role that microbes play in our health.

Microbes are microscopic organisms, like bacteria, viruses, fungus, or yeast. When we think of such things, we typically think of infections, but most microbes are harmless, and even helpful. The various microbes that live in our gut help us digest various foods, aid with nutrient absorption, and work to develop our immune systems. Increasing evidence also suggests that the gut, and the microbes that live there, can impact brain health. 

The gut is so closely tied to the brain that some scientists call it the “second brain”. This is because there is an extensive network of neurons within our gut that directly communicates with the brain through the vagus nerve. The vagus nerve is the main connection that controls the parasympathetic nervous system. Think of your parasympathetic nervous system as controlling “rest and digest” functions. It helps to regulate digestion, heart rate, and our immune system. 

From the Brain to the Belly: Why the Gut Matters in HD

We tend to picture HD as a one-way street, where the gene that causes HD produces a faulty protein that causes a decline in brain health. But it’s more like a two-way superhighway with lots of back and forth between the brain and the rest of the body, especially between the brain and the gut, referred to as the “gut-brain axis”. 

This road is busy with traffic lanes like the vagus nerve, immune cells, and the “second brain” of the gut. There are vehicles carrying chemical messengers made by gut microbes and border checkpoints such as the gut lining and the blood–brain barrier, which should only let safe travelers through.

In HD, problems at almost every point on this route can slow traffic, let dangerous cargo through, or disrupt communication entirely.

Roadwork and Weak Bridges: Barriers Breaking Down

HD’s faulty protein, expanded huntingtin (HTT), isn’t just in the brain, it’s everywhere, including the gut. This widespread presence may contribute to why people with HD often have symptoms in parts of their bodies beyond the brain, including gastrointestinal problems like chronic diarrhea, constipation, incontinence, and poor nutrient absorption.

Two major “bridges” on our superhighway are affected – the gut barrier and the blood-brain barrier. The gut barrier can become “leaky,” letting microbes or their components escape into the bloodstream. There is some evidence for this in people with the gene for HD before and after they start to show symptoms, seemingly at levels comparable to those in inflammatory bowel disease. 

The blood–brain barrier also shows signs of “loosened bolts” in HD, with fewer tight junction proteins holding it together. When both bridges are compromised, harmful substances from the gut could have a clearer route to the brain. Supporting this possibility, traces of bacterial and fungal DNA have been found in the brains of people with HD after death. While contamination is possible, it suggests that microbes, or at least parts of microbes, might be able to cross compromised barriers of the gut and brain.

Traffic Jams: Inflammation Along the Route

The gut is the body’s largest immune organ. In HD, this immune system seems stuck in overdrive, like a traffic jam of inflammatory signals. Cytokines, which play a role in regulating the immune response and inflammation, seem to be present at increased levels in blood from people with HD, years before symptoms start. Adding to that, higher levels of some cytokines appear to be linked with worse symptoms and lower scores that chart someone’s ability to carry out day-to-day tasks. 

But encouragingly, it seems that some beneficial gut bacteria may be able to dampen this inflammation, acting like traffic police to keep things moving. However more work is needed to understand the exact type of bacteria that could provide a benefit and if we could harness this as a future treatment option for people with HD. 

Inflammation is also seen inside the gut itself, with high levels of a biomarker that signals stress on the gut lining. 

Faulty Signaling: Vagus Nerve Disruptions

The vagus nerve is the main fiber-optic cable of the gut–brain superhighway. It carries both sensory updates from the gut to the brain and calming “anti-inflammatory” signals back down. In HD, low vagal tone, a sign of reduced nerve activity, seems to be present even 20 years before motor symptoms. 

Low tone could worsen inflammation and has been linked to depression, a common symptom of HD. Researchers are asking whether stimulating the vagus nerve could one day be a therapeutic on-ramp.

The Microbial Passenger List: Who’s in the Vehicles?

Studies are suggesting that the gut microbiome in HD has a different passenger list than in healthy individuals. Diversity may be lower, meaning fewer types of microbes, and certain species might be missing or reduced. Less diversity in the gut microbiome has been linked to lower immune function, poorer digestion, and fatigue.

While more work is needed, researchers are starting to tease apart the microbial differences in the gut of people with HD. For example, the presence of certain microbes may be linked to better thinking skills but worse motor symptoms. And there appears to be sex-specific differences in both humans and mice, suggesting men and women may have different microbes present. 

Possible Road Repairs: Interventions in the Works

If the gut–brain superhighway in HD has traffic jams and potholes, the big question is, can we fix it? Scientists are exploring various ideas to get traffic flowing more smoothly. One option is probiotics (adding “good” bacteria) or prebiotics (feeding the good bacteria already there). These are generally safe, but the first HD trial testing probiotics didn’t show big changes in gut health or thinking skills, so more work is needed in this area to know if this might be beneficial. It might be that we need longer treatment or different combinations of probiotics are needed to see an effect.

Food itself could be a powerful repair tool. In HD mouse models, a high-fiber diet seemed to boost thinking skills, lift mood, and improve gut health. But the most striking findings from this study compared a high-fiber diet to a no-fiber diet in mice, which isn’t realistic for people, who are more likely to consume a low-fiber diet by comparison. So more work would be needed to test this theory.

In people, following a Mediterranean-style diet that is rich in fruits, vegetables, whole grains, and healthy fats has been reported by some to improve quality of life and perhaps allow for fewer movement problems. Other diets, like the ketogenic (very low-carb, high-fat) approach or intermittent fasting, have shown mixed results and come with serious risks. It’s a reminder that there’s probably no one-size-fits-all diet for HD.

It’s not just about food, how we live also shapes the gut–brain connection. In HD mice, physical activity and a stimulating environment seem to delay disease onset and slow progression, while also changing the gut microbiome. Even certain antibiotics, if chosen carefully, have shown reduced inflammation and protected nerve cells in lab models. But broad-spectrum antibiotics, the kind that wipe out a wide range of bacteria, can cause long-term damage to gut diversity, so they’re not a realistic option for intervening with the microbiome.

An Overlooked Exit: Oral Health

After the gut, the mouth has the second largest microbial population within the body. While the effect of HD on the microbes in the mouth hasn’t been studied, we do know that as HD progresses, it can become harder to keep up with oral hygiene. This can lead to gum disease, cavities, and inflammation in the mouth.

That might sound like a small problem compared to the challenges of HD, but oral health affects the whole body. Inflammation from the mouth can spill over into the bloodstream, adding to the overall “traffic jam” of inflammation we already see in HD. Over time, this could make gut and brain problems worse.

The good news is that this is an area where we already have easy tools. Regular dental care, help with brushing and flossing, and even specially designed oral probiotics could all help keep the mouth’s microbial community balanced. These simple steps might not just improve comfort and quality of life, they could also help reduce inflammation that feeds into HD’s wider effects.

It’s a reminder that in a complex condition like HD, the most effective “road repairs” might come from surprising places. From the microbes in our gut to the health of our mouth, every stop along the gut–brain superhighway could hold clues, and opportunities, for improving life with HD.

Summary

• The gut–brain axis is a busy two-way superhighway of nerves, immune cells, and chemical messengers.
• In HD, barriers leak, inflammation surges, and microbial balance shifts, potentially influencing disease progression.
• Early studies suggest diet, probiotics, or exercise could one day help, but more research is needed.
• Oral health may be an underexplored but important off-ramp in managing HD’s systemic inflammation.

Learn More

Original research article, “The microbiota–gut–brain axis in Huntington’s disease: pathogenic mechanisms and therapeutic targets” (open access).