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

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)