This Fall, HDBuzz is proud to launch our “Falling Into Hope” fundraising campaign. Our goal is simple but ambitious: raise $30,000 in the next 8 weeks, by October 28.
2025 will be a landmark year in HD research. We’re closer than ever to disease-modifying therapies, and clear, unbiased reporting has never been more essential.
HDBuzz has grown in big ways in 2025 with the establishment of an independent advisory board, transitioning to our own 501(c)(3), updating our website, and expanding our social media reach. And, with your help, we have big plans for 2026! We want every person in the HD community, no matter where they are, to have access to reliable HD research, so we’re translating HDBuzz into more languages to reach more families than ever before and are training the next generation of science communicators. Gelgas Airlangga
Why Independence Matters
We’re thrilled to share that HDBuzz is now an independent 501(c)(3) non-profit organization in the US! This milestone marks our transition out of the fiscal sponsorship of the Hereditary Disease Foundation, who generously supported us for the past year. We’re deeply grateful for their role in helping us get here.
Now, as we step fully into independence, we need your support to keep HDBuzz strong and sustainable. Unlike many organizations in the HD landscape, we make a deliberate choice not to accept funding from pharmaceutical companies. That independence means you can trust us to remain unbiased, especially as we get closer to having disease-modifying drugs.
2025 will be a landmark year in HD research. We’re closer than ever to disease-modifying therapies, and clear, unbiased reporting has never been more essential.
What Your Donations Support
Every dollar raised through Falling Into Hope directly supports:
Transitioning to independence as a stand-alone non-profit
Maintaining unbiased reporting on HD science and clinical trials
Expanding global access, including automated translations into 10 languages by the end of the year
Training the next generation through the HDBuzz Prize writing competition
Reaching more families with the help of our new social media manager and updated website
Your donations don’t just keep the lights on. They ensure that HD families everywhere can rely on accurate, accessible science communication at this critical moment in history.
As we get closer to treatments that can modify Huntington’s disease, HDBuzz wants to ensure that we remain an unbiased, trusted source for the HD community to turn to when they need accurate news they can understand. Jakub Zerdzicki
A Trusted Global Resource
This year, we’ve built capacity in big ways: a new advisory board of leaders in HD research (Dr. Hugh Rickards, Dr. Vanessa Wheeler, Dr. Ray Truant, Dr. A. Jenny Morton), a WordPress upgrade behind the scenes, and expanded outreach through social media.
We’re also proud to showcase the 2025 HDBuzz Prize winners, early-career scientists who will publish their articles this month! Their work is a glimpse of the future — not just of HD science, but of science communication.
Unlike many organizations in the HD landscape, we make a deliberate choice not to accept funding from pharmaceutical companies. That independence means you can trust us to remain unbiased, especially as we get closer to having disease-modifying drugs.
Join Us: Fall Into Hope
The next 8 weeks will determine how boldly HDBuzz can grow in 2025 and beyond. Our mission is clear. We want to keep science communication accessible, unbiased, and global, no matter what breakthroughs come next.
But we can’t do it without you. Help us raise $30,000 by October 28. Your gift makes the difference between simply reporting on progress and ensuring every HD family, everywhere, has the knowledge they need to face the future with the knowledge they’ll need as we advance toward disease-modifying therapies.
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.
Research suggests that it wasn’t always physical abuse or big, traumatic events in childhood that predicted whether an individual from a family with Huntington’s disease would struggle with their mental health in adulthood. More often, it was emotional neglect or emotional abuse, things like constant criticism, hurtful words, or growing up in a home where emotions felt unsafe, unpredictable, or simply too hard to talk about.
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.
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.
Repetitive DNA sequences like the CAG repeat within the huntingtin gene that causes Huntington’s disease can form awkward loops, like a misplaced prop on stage. Normally, FAN1 helps tidy things up, but the R507H mutation makes it harder to keep the performance running smoothly.
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.
Repetitive DNA can form awkward loops, like a misplaced prop on stage. Normally, FAN1 helps tidy things up, but the R507H mutation makes it harder to keep the performance running smoothly.
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.
The insights from these studies were made possible thanks to HD families worldwide who contributed DNA samples to genetic studies.
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.
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.
Like an assembly line, the huntingtin protein can be built into different shapes. New research shows us the blueprint of its toxic fibres, and hints that we may be able to re-engineer them into safer forms.
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.
Curcumin, a natural compound found in turmeric, can subtly reshape huntingtin protein fibres in the lab, making them less harmful to brain cells.
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.
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.
Biomarkers can measure the progression of diseases like Huntington’s, acting like hurdles in a race. They let scientists and clinicians know if a treatment might be going well, or not.
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.
“Omics” studies examine all the components of a living thing, whether that be genes, fats, other molecules, or proteins. These detailed inventories have transformed what we know about Huntington’s disease and are advancing biomarkers studies.
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.
