May was a month packed with exciting research, and we’ve got the highlights ready for you – no lab coat required! From genetic mysteries to vision changes and dental awareness, researchers uncovered some fascinating stuff about Huntington’s disease (HD) this month. And we heard an exciting clinical trial update from PTC Therapeutics. Buckle up for an abbreviated tour through the latest discoveries that are helping us learn more about HD and getting us closer to a treatment. 

Assembly Line Breakdown: Protein Production Problems in Huntington’s Disease

New research put a spotlight on the world of protein production – and how things go a bit haywire in HD. A new study revealed that the mutant huntingtin protein doesn’t just misbehave on its own – it also messes with the cell’s entire protein-making factory. 

Imagine a broken part clogging up the assembly line, causing chaos everywhere! In HD, even a little bit of this rogue protein can throw off the cell’s finely tuned quality control systems. The researchers also uncovered a tiny control switch in the HTT gene that might crank up the dysfunction even further. The big idea? Instead of just focusing on the toxic proteins themselves, maybe we can fix the machines they’re jamming up.

What’s Good for Your Heart is Good for Your Brain: New Study Links Cardiovascular Health to Brain Aging

There seems to be a connection between heart health and brain health. A new study revealed that following the American Heart Association’s “Life’s Simple 7” guidelines – like eating well, exercising, and managing blood pressure – not only benefits your heart but also tracks with lower levels of neurofilament light (NfL), a protein that tracks with brain health, can indicate brain cell damage and has become an important biomarker in HD research. 

Specifically, participants with better cardiovascular health had significantly lower NfL levels, suggesting less neuronal damage. Over a decade, those with high heart health scores experienced a slower increase in NfL levels compared to those with lower scores. While the study didn’t find a similar connection with another biomarker, total tau , the findings underscore the potential of heart-healthy habits in protecting brain health, especially for those at risk of neurodegenerative diseases like Huntington’s.

Excitement and Anticipation as PTC’s Huntington’s Disease Drug Clears a Major Hurdle to Sprint Home

Perhaps the most exciting update from the month was the buzz-worthy news from the world of HD clinical trials! PTC Therapeutics’ daily pill, votoplam (formerly PTC-518), showed promising results in the Phase 2 PIVOT-HD clinical trial. The trial met its primary goal by effectively lowering levels of the huntingtin protein, a key strategy being explored in the clinic to treat HD. Importantly, votoplam demonstrated a favorable safety profile, with no serious adverse events reported. 

Additionally (and certainly most excitingly!), early data suggest potential benefits in slowing disease progression, particularly in individuals with Stage 2 HD, as measured by some biomarkers and clinical assessments. While further analysis is needed, these findings advance hope for a new, convenient potential treatment option for the HD community.

The next steps here are for PTC to dig into the data more, then go over it with their new partner, Novartis. It’s not clear yet if they’ll use data they already have to seek accelerated approval from regulatory agencies or dive into a larger Phase 3 trial for votoplam. We’ll be watching closely and keep you updated as we learn more!

From genetic mysteries to vision changes and dental awareness, researchers uncovered some fascinating stuff about Huntington’s disease (HD) this month.

Navigating the Genetic River: How Tiny Variants Could Shift the Course of Huntington’s Disease

New work this month took us on a journey down the genetic river of the HD gene. Researchers discovered that tiny changes – like missing or duplicated genetic “dams” in the DNA sequence – can dramatically alter the river’s flow, potentially shifting the onset of HD symptoms by over a decade. These rare variations, known as Loss of Interruption (LOI) variants, affect the stability of the CAG and CCG repeat regions in the HTT gene. 

While these genetic quirks are uncommon, they offer valuable insights into why some individuals develop HD earlier than expected, especially those in the diagnostic “gray zone” with intermediate repeat lengths between 27 and 29 CAGs. This research underscores the complexity of HD genetics and highlights the importance of understanding these subtle variations as we navigate toward more precise diagnostics and treatments.

Red Light, Green Light: How Huntington’s Disease Influences Genetic Traffic Lights

This month we took us on a ride through the genetic intersections of HD, revealing how the disease throws the cellular traffic system into chaos. Normally, our genes are regulated by epigenetic “traffic lights” – chemical signals that tell genes when to stop (red) or go (green). 

In HD, these signals malfunction, causing some genes, especially those involved in early brain development, to get stuck on green when they should be red. This misregulation leads to neurons acting like they’re in a perpetual developmental phase, potentially accelerating brain aging and dysfunction. 

The usual molecular “traffic cops,” PRC1 and PRC2, which are supposed to help maintain order, seem to be overwhelmed or replaced by less effective versions, making the problem worse. Understanding this epigenetic traffic jam opens new avenues for potential therapies aimed at restoring proper gene regulation and slowing disease progression.

Unlocking the Mind’s Eye: How Huntington’s Disease Changes How We See and Process the World

Another study zoomed in on something we often take for granted: how our brains make sense of what we see. For people with HD, recognizing faces, reading a book, or even navigating a grocery store can get surprisingly tricky. Researchers in Spain ran a bunch of clever visual thinking tests, like drawing shapes from memory, to find out when and how these challenges pop up. 

The plot twist? Subtle changes in visual memory might show up even before classic HD symptoms appear. This offers a chance for earlier diagnosis and better planning. Because it’s not just about what the eyes see, but how the brain interprets it. Spotting these shifts early could encourage people to use helpful visual reminders that could make a big difference in daily life.

DNA Repair in Huntington’s Disease: Not Up to Par?

More and more evidence is showing that HD influences DNA repair. A new study from Dr. Ray Truant’s team shows that expanded HTT slows production of a key DNA repair molecule called PAR, which usually flags damaged DNA. Without enough PAR, HD cells let damage pile up, possibly fueling the expansion of those nefarious CAG repeats that drive the disease.

The good news? Fixing the fixer might help. Getting HD cells up to par – by increasing PAR – could give cells the repair boost they need to fight back against disease progression. It’s early days, but this glitch in the repair crew might just point to a new way to keep Huntington’s in check.

Perhaps the most exciting update from the month was the buzz-worthy news from the world of HD clinical trials! PTC Therapeutics’ daily pill, votoplam (formerly PTC-518), showed promising results in the Phase 2 PIVOT-HD clinical trial.

Mind Your Mouth: Huntington’s Disease and Oral Health

HD can wreak havoc on oral health. A recent review reveals that people with HD face many dental challenges: movement issues make brushing a chore, dietary changes favor cavity-causing foods, and many dentists are unprepared for the unique needs of HD patients. Add in anxiety, financial strain, and mobility hurdles, and it’s no wonder dental care often gets sidelined. 

But there’s hope! The article emphasizes that with the right knowledge and preparation, dental professionals can make a significant difference. By understanding HD’s impact and adapting care strategies, they can help patients maintain healthier smiles and improve their quality of life. The fact that this review was published is evidence that the word about HD is spreading amongst the dental community. So, let’s give a shout-out to those dentists ready to tackle HD’s dental dilemmas head-on – because everyone deserves a reason to smile.

Seeking dental care and adhering to recommended routines is tough for lots of folks, even under the best of circumstances. Throw Huntington’s disease (HD) into the mix, and oral health can get even tougher. A recently published review paper in the journal Special Care in Dentistry covers some of the challenges faced by HD families with keeping our chompers healthy. It also discusses research into oral health in HD, and recommends strategies for dental professionals caring for people with HD. When specialists care enough to prepare and publish a formal article about improving quality of life through oral health for people with HD, we think that’s worth mouthing off about!  

Barriers to Dental Care 

The authors of this paper, Dr. Hanad Duble and Dr. Aviv Ouanounou, describe HD for their readers (dentists) who are unfamiliar with the disease, and outline common barriers to accessing dental care for people with HD. Some of these may seem obvious to the HDBuzz readers – those who are affected by HD, live with someone who is symptomatic, or are tuned into HD research. Here are some of the main barriers the authors identify: 

• Fear: A lot of folks dread the dentist, and that anxiety can be exacerbated for people with HD. Shame and stigma can compound this as well. 
• Finances: HD can create a financial strain for many reasons, including job loss and accompanying lack of insurance, and it can be hard to financially prioritize dental care.
• Mobility and motivation: Behavioral symptoms and movement challenges can make it difficult to get to a dental office, keep appointments, or maintain a routine at home.
• Oral changes: Involuntary movement (chorea), stiffness, or muscle weakness make it more challenging for dentists to examine, clean, and operate on the mouth. 
• Lack of training: Many dental professionals don’t have experience working with people with HD (this article is a step towards providing guidelines!)

There may be other barriers to proper oral care for individuals from HD families – no one experiences HD in the same way. The vast majority of dentists are unlikely to see more than a few HD patients over a lifetime of practice, so it’s encouraging when knowledgeable professionals write about the challenges of HD for their peers. 

Seeking dental care and adhering to recommended routines is tough for lots of folks, even under the best of circumstances. Throw Huntington’s disease (HD) into the mix, and oral health can get even tougher.

Common Oral Health Challenges

The authors also lay out common oral challenges for people with HD and how they affect dental care. They drew from their own practice as well as from the scientific literature, including clinical studies, case reports, and past reviews. It’s a lot to sink your teeth into, but important to know what might arise as symptoms progress. 

Cavities (caries) and gum disease: 

• Chorea: movements of the body, face, and tongue can make it more difficult for a person with HD or their companion to brush and floss, and dentists may have trouble using specialized tools or finding safe and comfortable positions. 
• Diet: a person’s eating habits might change to accommodate chorea, difficulty with chewing and swallowing, or weight loss. Softer foods, liquids, higher frequency of meals, and foods with more sugar and carbs can affect tooth and mouth health.
• Dysphagia: the medical term for difficulty swallowing, which is very common in HD. This can mean that more food gets stuck in the teeth, mouth, and throat.
• Mood and motivation: symptoms like apathy and depression can make it more difficult to prioritize oral care at home or make dental appointments.

Medication challenges 

• Side effects: some of the drugs used to manage HD symptoms, like antidepressants and mood stabilizers, can cause dry mouth, drooling, or increase the risk of mouth infections. Other medications can cause increased likelihood of fainting or dizziness, which is important for a dentist or hygienist to be aware of when using a reclining chair or choosing anesthetics. 
• Drug-drug interactions: some medications prescribed to treat dental pain, anxiety, and infections can interact negatively with common treatments for HD.
• Anesthesia: general anesthesia can lead to complications, especially with chronic disease, so specialists may choose sedation over “putting someone under.” 

Dysarthria (difficulty speaking) 

• Home care and appointments: also known as dysarthria, when someone has a hard time communicating, it can be difficult to let a loved one or dentist know what is causing them pain or discomfort on a daily basis or during an appointment.
• Placement of devices or prosthetics: muscle weakness in the face and tongue that causes difficulty with speech can also make it difficult to keep safety devices or prosthetics (false teeth) in place. 
• Consent: some people might want to request or deny aspects of routine care or invasive procedures, and communication challenges can make these discussions slower or impossible. 

Strategies for dental care

This paper provides recommendations for dentists who are treating people with HD, based on a thorough understanding of published evidence, as well as the authors’ years of collective experience in this field. It may be helpful for families to “brush up” on what special precautions, procedures, and work-arounds are available.  

• Compassion and presence (duh!): the authors urge dentists not to discriminate against HD patients, and they note that a good rapport, emotional support, and care partner involvement can be especially helpful to ease anxiety and motivate a routine.

• Planning for dental care: making a longer-term plan for dental care early on can be helpful to discuss concerns and wishes around diet, role of a care partner, and how to approach daily care or procedures when communication becomes more difficult. 

• Extra prevention:
  • The paper recommends that dentists assign an oral hygiene plan and emphasize caregiver involvement and education. 
  • Dentists might consider fluoride or varnish treatments for adults, though they are normally given to kids. 
  • Consuming products with xylitol (a sugar substitute in some types of candy, mouthwash, and toothpaste) can be good for teeth
  • Mouthguards can relieve grinding pressure due to chorea. 
  • More frequent visits (every 3 or 6 months) if possible may help to keep teeth healthier and adjust care plans as needed. 

• Comfort and safety:
  • If a person is taking medications that cause a sudden drop in blood pressure when sitting or standing, the authors recommend avoiding reclining the dental chair past 45 degrees, and not sitting them up too fast.
  • Pain control: choosing acetaminophen (paracetamol) over ibuprofen is safer for those taking SSRIs.
  • Dentists can consider using medications that keep the patient awake but relaxed to minimize pain or control chorea for long appointments or procedures. 
  • Dental offices might have (or may be able to order) special chairs, restraints, biting devices, or pillows that help to keep someone comfortable and stable and their mouth positioned safely during an exam, cleaning, or procedure.

• Less invasive care:
  • Brushing/flossing alternatives exist to make care easier, like water flossers, floss picks, or different types of brushes. 
  • Preventing damage: if someone with HD has many small cavities that might require a lot of fillings, the authors recommend that dentists consider painting teeth with Silver Diamine Fluoride, which can kill bacteria and stop existing cavities from worsening. 
  • Filling material: there are different substances that dentists use to fill cavities. One recommendation in this paper for treating people with HD is the use of a filling made of Glass Ionomer (GI). This is often used on baby teeth, or as a temporary solution in adults. It doesn’t last many decades the way a metal or composite filling can, but it is easier to apply and releases fluoride. 

Extra care and planning early on can help delay the need for tough conversations and complex procedures later.

Lots to chew on

First and foremost, the existence of this publication is encouraging. It’s a new reference that consolidates information and practical advice, with the goal of helping professionals better understand HD-specialized dentistry. However, we are not presenting medical advice! Please consult with your own dentist before embarking on any new oral health regimen. The more info they have about other aspects of your health and medical history, the better individualized care they can provide. 

That said, the authors of this paper stress prevention and early communication. Extra care and planning early on can help delay the need for tough conversations and complex procedures later. They recommend that dentists caring for people with HD consult with each patient’s neurologist, understand the side effects of common HD medications, and provide comfort measures and plans tailored to the individual. You may be able to help jump-start those important conversations and connections.  

Above all, we encourage each member of every HD family to take care of their pearly whites and to advocate for their needs – healthier mouths make for louder voices!

Learn More

Original research article, “Huntington’s Disease and Dentistry: A Review of Its Etiology, Clinical Presentation, Symptomatic Pharmacotherapy, and Dental Management” (open access).

Scientists are working to understand some of the earliest changes to DNA repair caused by Huntington’s disease (HD) – insights that could help uncover new therapeutics and new ways to target somatic expansion, a key driver of disease progression. A molecule that helps fix DNA damage – called PAR – is lower than expected in people with the HD gene. This suggests that cells may struggle to properly repair their DNA  from the natural wear-and-tear damage that happens everyday to DNA. These findings could have implications for changes in the DNA repair process that drives somatic instability. The discovery could help researchers explore new ways to protect brain cells by boosting the cell’s natural repair systems.

Genetic Mutations and Repairs

The term genetic mutation gets thrown around quite a bit, but what does it actually mean? In short, a genetic mutation is any change to the letters of DNA – the cell’s instruction manual for building proteins. These changes can alter how the genetic code is read and used by cells, sometimes disrupting the function of proteins, the cell’s molecular machines. One striking example are mutations in the HTT gene, which significantly disrupts the activity of its coded protein, leading to HD. 

While the mutation that causes HD is inherited at birth, our cells also collect new mutations as we age. The consequence of these random age-related mutations is difficult to predict, but generally speaking, they contribute to age-related diseases like cancer and neurodegeneration. Fortunately, these age-related mutations are normal and are mostly repaired and fixed before they cause problems. 

But unfortunately, this process is not working right in HD. Previous studies have noticed that cells from people with the gene for HD tend to build up more mutations over their lives, likely a result of faulty DNA repair machinery. Faults with the DNA repair machinery lead to somatic expansion, a biological process that increases the CAG repeat length in the HTT gene in some cells over time. A new study led by Dr. Ray Truant and his team at McMaster University investigated how the HD mutation disrupts DNA repair and identified a prime suspect: defective PARylation. 

A Broken Spell Checker

Cells are equipped with sophisticated systems to fix DNA damage, and one key pathway is PARylation. PARylation involves building long chains of a molecule called PAR (Poly-ADP-Ribose) on regions of damaged DNA. These long chains act like molecular handles for DNA repair enzymes to latch onto and begin fixing the DNA. In this way, PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations. 

To investigate, Truant’s team first analyzed the amount of PAR chains in the spinal fluid, a substance that bathes the brain, from people with HD. Because PAR chains are produced in response to DNA damage, and people with HD have higher levels of DNA damage, they expected to find more PAR chains. 

However, what they found surprised them – people with HD had fewer PAR chains. This paradox was then examined using cells from people with HD, which did not show elevated levels of PAR chains despite having elevated levels of DNA damage. These results suggest that the machinery for building PAR chains, and thus repairing DNA, may not be able to keep up with demand!

PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations.

Not On PAR

Why might there be fewer PAR chains in HD cells despite having more DNA damage? To figure out why, the researchers needed to examine the underlying protein machinery. PARylation relies on two key enzymes: PARP, which builds PAR chains to initiate DNA repair, and PARG, which cuts them up once repairs are complete. 

So the researchers asked, is PARG overactive? Or is PARP underperforming? After some careful biochemistry, they found the latter seems to be true – PARP activity seemed to be reduced in HD cells, explaining the shortage of PAR chains and perhaps the increased rates of mutation. 

The team then turned their attention to HTT. Since the HTT protein acts as a scaffold, binding to lots of other proteins, they wondered if the mutated version that causes HD might interfere with HTT interacting with PARylated proteins. Because PAR chains also form on proteins in addition to DNA, they compared the proteins that HTT is known to interact with to the proteins known to be PARylated. They found that nearly half of the proteins that HTT interacts with are also PARylated.

This raises the suspicion that HTT itself could be modified by PAR. If it is, and this process is altered by mutant HTT, it might explain the differences in the PAR chains they saw in HD cells. 

HTT and PAR Chains

To test if HTT interacts with PAR chains, the team used a high-tech microscope to track where HTT and PAR chains are found in living cells. Although PAR chains and HTT did not overlap most of the time, they did overlap on chromosomes when cells divide. 

Additionally, when they turned off PAR chain production by blocking PARP activity, HTT no longer overlapped, suggesting that PAR chains might be guiding HTT to chromosomes during cell division. Although the importance of HTT and PAR chains overlapping during cell division was not investigated further, it does suggest there could be a functional interaction between them! 

To strengthen their case, the researchers used a couple more techniques to confirm the interaction between HTT and PAR chains. First, they looked closely at the molecular structure of the HTT protein and found many slots that looked like they could fit a PAR chain. Then, using a high-resolution microscope, they directly visualized the PAR chains produced by PARP with and without HTT present. They noticed PARP produced far more elaborate PAR chains when HTT was around, suggesting that HTT was stimulating PARP activity. Importantly, mutant forms of HTT did not have any stimulating effect on PARP activity, possibly explaining the reduced production of PAR chains in people with HD. 

In cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration.

Implications for HD and Beyond

These findings paint a clear picture: in cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration. 

These findings are exciting because they help researchers better understand the underlying defects in HD cells, but perhaps more importantly, they open up therapeutic possibilities. 

Much of the interest surrounding PARP is due to the publicity it has received in an entirely different domain of research – cancer, where dozens of molecules targeting PARP have already been teased out. Because drugs designed to modulate PARP activity have already been tested for safety, they could potentially be repurposed for HD, accelerating its path to clinical trials. Although any repurposed drugs would still need to be thoroughly tested, this research opens up exciting new therapeutic roads that may address the issue of mutations building up, a critical problem with cells in HD.

Learn More

Original research article, “Poly ADP-ribose signaling is dysregulated in Huntington disease” (Open access).

Imagine waking up one day and realizing that the world around you no longer looks the same. Faces are harder to recognize, navigating familiar streets feels confusing, and reading a book becomes a frustrating puzzle. This unsettling scenario is a reality for many people affected by Huntington’s disease (HD). Dr Juan Carlos Gómez-Esteban and his team of researchers from Spain, investigated if HD affects the brain’s ability to process and understand what people can see. They also researched when these changes in processing and understanding occur in people with HD. 

Bringing HD Into Focus

You might be wondering why is it important to focus on how people with HD see and understand things? This is because the part of the brain that is most affected by HD, called the striatum, is not just responsible for controlling movement – it also helps the brain process and understand what we see. As HD progresses, it becomes more and more difficult for the brain to handle visual information, making everyday tasks that used to be second nature, more and more challenging.

Picture trying to cross a busy street but struggling to judge how fast cars are moving. Or meeting an old friend but not recognizing their face right away. These are the kinds of frustrating, everyday obstacles that can come with visual thinking problems in HD. Understanding these challenges is crucial, not just for diagnosing HD earlier, but for developing therapies and treatments that help people with HD, navigate the world more confidently and independently.

Seeing the Early Signs

This study involved 181 participants, including people spanning different stages of HD. Beside each stage, we included the Huntington’s disease Integrated Staging System (HD-ISS) that best describes these categories. For more information on HD-ISS categories, please see our article about this system. A control group of individuals who do not have HD were also recruited to the study. This is because the researchers wanted to find out whether HD affects visual thinking skills, and if so, when these changes begin. People with HD were grouped into one of four categories for the purpose of this research:

Category 1 – People who have had the genetic test for HD and have a reduced penetrance allele (slightly lower number of CAG repeats, spanning 36-39 CAGs). This means that it is uncertain if these individuals will or will not go on to develop the symptoms of HD in their lifetime.

Category 2 (similar to Stage 0 of the HD-ISS) – The person has tested positive for HD (CAG number is 40 or more) but does not yet display any recognisable symptoms.

Category 3 (similar to Stage 2 of the HD-ISS) – The person with HD begins to experience symptoms. There may be noticeable changes in their motor abilities, mind, and mood symptoms. The individuals affected may still be fairly independent at this stage.

Category 4 (similar to Stage 3 of the HD-ISS) – The person with HD experiences fully developed HD symptoms, which significantly impacts their daily life. Individuals at this stage require significant support with their activities of daily living.

As HD progresses, it becomes more and more difficult for the brain to handle visual information, making everyday tasks that used to be second nature, more and more challenging.

Measuring What the Eyes Cannot See

To investigate if HD affects visual thinking skills (the brain’s ability to process and understand what people with HD can see), participants completed a variety of tasks that could measure these skills. These tasks assessed different ways people see and understand things. For example: remembering what we see; understanding where things are and how they move; focussing on what we see; how quickly we make sense of what we see.

But what tasks were used to measure these abilities? How well participants could remember what they see, was assessed by asking participants to copy a shape presented to them by drawing it. After a small amount time delay, the participants had to draw this shape again, from memory. Another example of a task that measured how well participants could remember what they see, involved showing participants a set of different shapes. After, the participants had to remember what shapes they were shown, and in what order they were displayed.

The team of researchers also investigated how well the brain was functioning, more generally. Brain functioning was assessed in each participant by performing tasks that measured vocabulary skills, attention levels, and problem-solving abilities. It was important to include these more general measures to understand how the brain’s ability to understand what people can see may ‘fit’ into wider brain functioning.

Together, the variety of tasks performed helped Dr. Gómez-Esteban and his team to build a better picture of how visual thinking abilities change in people with HD who are at different stages of the condition, as well as compared to individuals who do not have HD.

Through the Lens

Here’s the twist: Dr. Juan Carlos Gómez-Esteban and his team did not find any major differences in general thinking skills between people who did not have HD, people with the reduced penetrance allele (Category 1), and people who have tested positive for HD, but do not yet display any symptoms (Category 2).

But here’s where it gets interesting: visual memory abilities (think back to the task involving drawing shapes from memory) differed between the groups in this study. People with reduced penetrance (Category 1) had greater visual memory abilities compared to people with HD, who do not yet display recognisable HD symptoms (Category 2).

What’s even more intriguing is that when looking at people with HD experiencing early symptoms (Category 3) and people experiencing fully developed HD symptoms (Category 4), visual memory abilities remained relatively unchanged. This could suggest that a change in visual memory abilities could be one of the first signs of changes in thinking in people with HD. This could make visual memory skills a valuable clue in spotting HD early on.

It’s not just about what the eyes see – it’s about how the brain makes sense of it. Understanding this connection could make all the difference.

Seeing the Bigger Picture

Understanding how HD affects the brain’s ability to make sense of what we see could lead to an earlier diagnosis of HD and better treatment options. If having reduced visual memory abilities tends to appear before motor symptoms, testing for this could help to identify signs of HD sooner in individuals giving them more time to plan and seek support.

Visual memory changes could be an early warning sign of HD, offering a chance for earlier diagnosis and treatment. It’s not just about what the eyes see – it’s about how the brain makes sense of it. Understanding this connection could make all the difference.

Spotting visual memory changes in people with HD is not just about early diagnosis, it’s about making life better. So, if you or your loved one with HD can be forgetful when trying to remember a familiar face, keeps losing their phone or glasses, or keeps getting lost in the grocery store, you could consider using some helpful visual reminders.

Learn More

Original research article, “Characterization of visual cognition in pre-manifest, manifest and reduced penetrance Huntington’s disease” (open access.

For Huntington’s disease (HD), a lot of attention goes to the genetic change that causes HD, but new research is shining a light on something else – our epigenome. The word literally means, “above” the “genome”, or above the genetic code. It’s a layer of chemical marks that are added to genes to regulate their activity. Think of the epigenome like a traffic control system for our genes. It’s responsible for deciding when a gene should “go” (get activated) or “stop” (stay quiet). When things go awry, like in HD, that traffic system breaks down.

Genetic Traffic Lights

Imagine a busy intersection – traffic is carefully orchestrated with different colored lights, telling drivers when to stop and when to go. If a signal turns yellow, drivers know that the light is in a transition between letting those cars go, and telling them to stop. These yellow lights are similar to what scientists call “bivalent” marks.

Bivalent genes carry both activating signals (the green light) and repressive signals (the red light) at the same time – like a yellow traffic light. This allows the gene to be ready to turn on quickly when needed, but also to stay off when it’s not. In HD, something goes wrong with these bivalent marks.

Stuck on Green

A surprising finding from this new work, led by Karine Merienne from the University of Strasbourg in France, is that certain genes that are normally “turned off” are staying “on” in the neurons of mice that model HD. The repressive signal (the “red light”) is lost, and the gene becomes more likely to turn on, as if the green light is stuck on. This means that genes which generally stay quiet in brain cells can get activated when they shouldn’t, potentially causing harm to the neuron.

Those stuck green signals are happening in genes that are involved in the early development of the brain. These are genes that help guide how a neuron develops and what kind of neuron it becomes. In a brain without HD, these genes are turned off after the brain develops, but in HD, they seem to be active for longer.

This is similar to what others have recently found, with data suggesting that HD may lead to genetic changes that cause certain brain cells to lose their identity, turning off genes that help define them as unique types of neurons. Until now, we didn’t really know how this might be happening.

The changes defined by Karine’s team were seen in HD mice, where developmental genes – key players in brain development – were activated in mature neurons. These persistent green traffic signals can make them more accessible for activation, which researchers think could contribute to problems in how neurons function.

“Traffic Cops”

There are special molecular machines in the cell that normally help keep this process in check, two of which are called PRC1 and PRC2. These complexes act like traffic cops, ensuring that genes stay in their proper lanes – some genes should stay off, and others should be on at the right time. PRC1 and PRC2 usually help maintain the “red light” by placing repressive marks on genes, keeping them quiet.

But in HD, it seems like these traffic cops are being overwhelmed. The “red light” is no longer functioning properly, and the genes that should stay quiet (the developmental genes) are getting the green light to turn on. This leads to those genes being active when they shouldn’t be, which could cause the neurons to behave inappropriately.

Researchers have discovered that PRC1 isn’t just losing its repressive marks, but the proteins it relies on to work, seem to also be switched out for less mature versions. Think of it like the traffic cops being replaced with rookie officers who aren’t as good at controlling the traffic. This shift could be a major reason why PRC1 is less effective at stopping the activation of developmental genes seen in the mouse model of HD.

A Building Traffic Frenzy

One of the most interesting findings is that this disruption doesn’t just happen all at once – it gets worse over time. As the HD mice age, more and more genes begin to be activated inappropriately. It’s as if the “green lights” keep getting stuck on, while the “red lights” continue to fail. The researchers suggest that this progressive breakdown of genetic traffic regulation may cause the neurons to age much faster than they would in a brain without HD. It’s like the cells are “aging” more quickly on a genetic level, which might underlie an earlier decline in their function.

Researchers followed these changes in HD mice and found that over time, the number of genes showing altered epigenetic marks kept increasing. In particular, they saw developmental genes becoming more active as the mice aged. Adding to that, they saw this effect specifically in neurons in the striatum, the part of the brain most affected in HD.

In these cells, the epigenetic marks that normally keep these genes in check were decreasing, while marks that signal activation were increasing. It’s as if the brakes were failing, and the gas pedal was stuck to the floor – such frantic driving would rapidly age most people!

Fixing the Traffic System

Understanding how these epigenetic changes contribute to HD opens up exciting possibilities for new treatments in the future. If we can find ways to correct the breakdown in PRC1 and PRC2 function, or restore the balance of the red and green lights at the level of gene regulation, we might be able to slow progression of the disease.

For example, therapies could aim to fix the loss of repressive marks, which would restore the “red light” and keep developmental genes from turning on inappropriately. Other treatments could target the switch in PRC1 proteins, making sure the “mature” traffic cops are in place, keeping the genes under control.

Furthermore, therapies that address the accelerated aging of neurons could help protect the brain from the damage caused by these epigenetic changes. By slowing down the “epigenetic aging” process, we might be able to prevent the brain cells from losing their function too quickly.

Red Lights Ahead?

The discovery of accelerated epigenetic aging in HD gives us a fresh perspective on the disease and offers hope for new treatment strategies. By understanding the role of bivalent promoters, and the malfunctioning PRC1 and PRC2 complexes, researchers could be uncovering how neurons in HD may age prematurely and lose their function.

This new knowledge not only improves our understanding of how HD progresses, but it also opens up the possibility of therapies that could target the underlying epigenetic changes. While there is still much to learn, these findings mark an important step forward in the search for ways to pump the brakes on Huntington’s disease.