We wrote in August of 2023 about the US approval of a new drug to treat chorea, the movement symptoms of HD. That drug, valbenazine, commercially known as INGREZZA, has just been approved in a new format, one that can be added to soft foods. This news deserves a brief HDBuzz mention.
Chorea control
Valbenazine is one of a few drugs known as VMAT2 inhibitors. These treatments act on a chemical messenger called dopamine in the brain to reduce the involuntary movements of HD (chorea). VMAT2 inhibitors used for HD include tetrabenazine, deutetrabenazine (AUSTEDO), and valbenazine (INGREZZA), but there are a variety of other treatments prescribed to people with HD who experience chorea. A doctor might prescribe one over another based on a number of factors, including availability, cost, side effects, and control of other mood and behavioral symptoms.
Solutions for swallowing
These drugs are taken by mouth, but as symptoms like chorea and changes in muscle control worsen, many people with HD can experience difficulties with swallowing. Therapy sessions with an experienced speech language pathologist (SLP) can provide best practices and safety guidance around eating for those in the later stages of HD. But sometimes it’s just too much of a challenge for someone to swallow a pill.
In these circumstances, common across many diseases, medical professionals might recommend that a person’s medication be crushed or dissolved. They’re not always designed to be delivered this way, but it’s a good solution for those who have an easier time with soft foods, liquids, or who use a feeding tube.
A sprinkling of good news from Neurocrine
Simply put, the news from Neurocrine Biosciences, the company that makes valbenazine is that they have created and received approval in the United States for a new formula called INGREZZA SPRINKLE, which comes in a capsule designed to be opened and added to soft foods. As we mentioned when we talked about the original FDA approval, this drug is currently only available in the USA, and Neurocrine has not yet made plans to seek approvals in other countries.
So valbenazine is not new, and the idea of opening or crushing a capsule to help someone with HD continue taking a helpful treatment isn’t new either. But US government approval of a new formulation of an HD drug is a good reason to celebrate – and we’ll take any excuse we can to eat ice cream.
HDBuzz strives to be an honest and neutral source of information that Huntington’s disease (HD) families can turn to for trusted, unbiased reporting on research and clinical trial news. We’re honored to have become a global resource for the HD community over the years (14!) and we look forward to building upon the original mission of HDBuzz as we head into a new era. Read on to learn more about the new editors-in-chief and our plans for the transition.
The need for information
While we know it’s hard to fathom at this point, there once was a world before Google. In those dark ages, information was harder to come by. This was especially true for HD.
Often, the most people heard about HD was restricted to short blurb in a textbook, distilling HD down to a disease passed from generation to generation that one had a 50% chance of inheriting if their parent was affected. This limited picture was particularly disheartening for HD families seeking information. Seeking answers. Wondering what research was being done to find a treatment for this devastating disease.
The broad establishment of the internet changed the way information could be shared. It promised greater accessibility of cutting-edge research. It provided a platform that could be used to immediately share information from one corner of the globe to another – from the lab bench to HD families. But what was out there was often hard to find, full of jargon, and interspersed with misinformation.
The advent of HDBuzz
Two HD researchers saw the gap in getting accurate information from researchers to the people most eager for scientific updates on HD – HD families. In 2010, Dr. Ed Wild and Dr. Jeff Carroll established HDBuzz to rapidly disseminate high-quality HD research news to the global community, written in plain and accessible language, by HD clinicians and scientists.
HDBuzz has gone to great lengths to be impartial in our reporting.
We don’t accept funding from any drug company or organization with a vested interest in a particular treatment or technology
No funding organization gets any editorial control over HDBuzz content
Independent external advisors provide input on content to ensure that it is impartial, scientifically accurate, and understandable
All our authors make disclosure statements, which they review whenever they contribute new content to ensure any possible conflicts are clearly declared
New HDBuzz Editors
As Ed and Jeff advanced in their careers, their research and consulting responsibilities increased. This left them with less time to support the vital mission of HDBuzz. To ensure HD families could continue to rely on HDBuzz as a trusted resource for HD news, the team grew.
A decade after HDBuzz’s creation, in 2020, Ed and Jeff folded in 3 new editors: Dr. Rachel Harding, Dr. Sarah Hernandez, and Dr. Leora Fox. If you’ve been reading HDBuzz articles over the past 4 years, you’ve likely seen these names in the by-line.
After 4 years of having Rachel, Sarah, and Leora on team HDBuzz, Ed and Jeff are officially passing the baton and stepping back to an emeritus role. This will allow them to focus their efforts on HD research and care, advancing promising ideas and experimental treatments for HD toward the clinic and give the new team the opportunity to grow and develop HDBuzz even further.
Meet your “new” Editors-in-Chief
So who exactly are the new names behind HDBuzz and why should you look forward to hearing their take on HD research in the years to come?
DR. RACHEL HARDING
What got you into HD research?
I have always been interested in understanding the precise molecular details of how biology and disease work; how do different proteins work together to perform a specific biological function and what molecular changes happen in disease for things to stop working properly? I was intrigued by HD as we know the exact molecular change which causes disease, an increase in the CAG number of the huntingtin gene DNA, but even with this knowledge, unpicking the molecular details or exactly what goes wrong has proved very challenging for the field.
In 2018, I was fortunate enough to be awarded a Huntington’s Disease Society of America Berman Topper Family Career Development Fellowship, which helped fund my research looking into the HD protein and how this molecule is changed in disease. I became hooked on trying to answer this question, and it has become the focus of my research ever since.
It very quickly became apparent just how welcoming and collaborative the HD research community is, and I feel lucky to be able to work with so many fantastic folks. The impressive way HD meetings and conferences span patient viewpoints, clinical trial updates, cutting-edge breakthroughs in the lab and everything in between, is just super.
What’s your “real” job?
I am a Principal Investigator at a research institute called the Structural Genomics Consortium (SGC) in Toronto. I wear a second hat as I am also an Assistant Professor in the Department of Pharmacology and Toxicology at the University of Toronto, Canada.
What this all means is that I run a research group who are primarily focussed on studying the HD protein, to better understand how it works, and what goes wrong in disease. As part of the SGC, we are also involved in many early-stage drug discovery research programs, in HD and other diseases.
The work we do is highly collaborative and we have partnerships with lots of different HD labs and other specialists around the world. Open science is a key part of our ethos and we share both our results and the materials we make and study in the lab, including the HD protein, with different labs that span all continents.
Why are you excited about bringing HDBuzz forward?
It has been such an honour to write, edit, present, and report for HDBuzz in the past few years. I have learnt so much about the HD community and it has reinforced my beliefs that science should be for everyone, and that it is critical that everyone has access to the latest research findings in plain language.
In this next phase, I am excited to build upon the great foundation created by Ed and Jeff, and push HDBuzz further. I am especially keen to connect with even more HD communities from around the world and further increase the accessibility of HD research to everyone who needs it.
DR. SARAH HERNANDEZ
What got you into HD research?
“Huntington’s disease” has been a household phrase for me since I was about 12 years old. That’s when I found out my maternal grandmother died from HD. I grew up watching family members suffer with HD, knowing what it meant for the next generations if something wasn’t done. That really lit my curiosity. From then on, I wanted to learn as much as possible about HD and how we could solve this problem so that we could get a treatment.
It turns out I had a whole lot more questions than there were answers! Ultimately this led to me getting a PhD in Biology with the hopes of helping to find a treatment. I did my postdoc with Dr. Leslie Thompson at the University of California, Irvine. She’s a pioneer in HD research – she was a member of the team that went to Venezuela to identify the gene that causes HD.
With Leslie, I used stem cells to model HD. We’re able to turn those cells into brain cells and ask and answer all sorts of questions about how the gene that causes HD is specifically affecting brain cells. I also worked with fruit flies that carried the HD gene to do genetic experiments.
What’s your “real” job?
About 2 years ago I started working at the Hereditary Disease Foundation (HDF) as the Director of Research Programs. The HDF was started by the Wexler Family, who is also affected by HD. Dr. Nancy Wexler has really changed the face of HD research, instilling collaboration into the field that has moved mountains. She led the missions to Venezuela to find the gene that causes HD.
At the HDF, I coordinate our scientific programming through webinars, workshops, and conferences. I also manage the grants program. Finding a treatment for HD is the primary mission of the HDF, and we believe that will happen through research. In 2023 we spent 85% of all donations on research. In 7 years, we’ve given over $13M in grants and fellowships to over 100 recipients!
I love the work that I get to do at HDF because I get to help support amazing researchers and see all the latest HD research as scientists are coming up with it. It’s the perfect job for me! My 12-year-old self would be pumped to see where I am.
Why are you excited about bringing HDBuzz forward?
The mission of HDBuzz really speaks to how I felt when I first found out HD runs in my family. When I was a kid, I just wanted answers about HD. I wanted to know about the latest research. I wanted to know what people were doing out there to get us closer to a treatment. If HDBuzz had been around back then, it could have saved me a lot of time (like, a whole PhD’s worth!).
I’m excited to bring HDBuzz forward because I know how HD families feel that just want to know what’s going on. I feel like scientists have a duty to get the information they find to the people that are affected by that information. The research project isn’t over until information gets where it needs to go. HDBuzz has been a fantastic resource for the HD community in ensuring that happens.
I spent 22 years in classrooms and at the lab bench developing the tools and skills that enable me to help people understand the science behind what’s going on in HD. I’m honored to be the conduit to get information about the research to the HD families who need it most.
DR. LEORA FOX
What got you into HD research?
I grew up volunteering (singing and dancing, actually!) in long-term care facilities where I became aware of a lot of neurodegenerative diseases, including HD. I was also one of those high school science nerds who started working in a lab as soon as someone would let me. This combo led me to study neuroscience in college, work in an Alzheimer’s lab afterwards, and eventually to pursue a PhD in neuroscience at Columbia University in New York City.
I was lucky enough to land in the lab of Ai Yamamoto, who was one of the first scientists to show that “turning off” the HD gene could lead to improvements in HD mice. She introduced me to the HD research community and gave me opportunities to write and speak in addition to designing experiments.
What’s your “real” job?
I’ve been at HDSA since 2016, and since 2021 I’ve overseen research and patient engagement programs. HDSA funds research, communicates about research, and helps to bring family voices into the drug development process. We are the largest family-facing HD organization, and we primarily serve the US.
In addition to research we support more than 60 multidisciplinary HD care centers around the USA, and we have a variety of advocacy initiatives, educational programming at the local and national level including our yearly HDSA Convention, the largest global gathering of HD families. We provide many different types of social services through our network of 100+ social workers, support groups, disability services, and other national and local programs.
Research plays into many aspects of support and care and vice versa, and I am constantly learning from the community members I speak to and from my colleagues in social services.
Why are you excited about bringing HDBuzz forward?
I like to say that my passion is helping people understand science, and helping scientists understand people. Bridging community needs with stellar research and presenting it in a way that everyone can understand is key to perpetuating the search for treatments.
I did not enter this field with a personal connection to HD, but this community, the families and the scientists, have become very dear to me. I love to write and edit, to engage with all sorts of people, to enable cross-talk and access and inquiry, to see research progress and to communicate its importance.
To be able to apply a hard-won skillset to help make HD science accessible, even entertaining, within a global community I care about – what a dream!!
What we’re dreaming of doing
HDBuzz has a solid foundation thanks to Ed and Jeff, and we are building upon their efforts to strengthen and expand upon the HDBuzz mission. Here are some of the steps we are taking towards that goal:
Get feedback from the global HD community about information needs, perceptions, and ideas for HDBuzz
Increase our pool of scientist-writers to include a diversity of voices
Integrate AI translation for global accessibility by having all articles available in as many languages as possible
Plan site updates and ongoing content based on community feedback
Thank you to Ed and Jeff!
As the new editors-in-chief of HDBuzz, we give our warmest, most heartfelt thank you to Ed and Jeff for what they created in HDBuzz. You’ve created an invaluable resource for the community that has shaped the way HD families receive news about ongoing research and trials. We look forward to continuing your mission as we usher HDBuzz into the future!
Drug hunters have been particularly interested in the repeating C-A-G letters of genetic code that lead to Huntington’s disease (HD). The number of CAG repeats gets bigger in vulnerable brain cells over time and may hold the key for slowing or stopping HD. Many scientists have been asking what happens to HD symptoms if we stop this expansion. Recent work from a group in London led by Dr. Gill Bates examined exactly this, seeking to define the threshold of CAG repeats needed to cause disease. Let’s discuss what her team found!
We’re all just alphabet soup
The genetic code of every living organism is made up of only 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body. That’s a lot of diversity for just 4 letters!
Within the huntingtin gene that leads to HD is a stretch of repeating C-A-G letters. People with HD are born with 36 or more CAG repeats in the huntingtin gene. As a person grows older, we know the number of CAG repeats can shift and wobble in some cells, getting bigger over time.
This ongoing CAG expansion is called “somatic instability”. This specifically happens in brain cells damaged by HD. It’s important to note that the CAG repeat size is relatively stable in blood. So a blood test showing 42 CAGs at the age of 18 will very likely still show 42 CAGs at age 50. But the brain cells of that person could have more than 100 CAG repeats, and a few may even have 200 repeats or more.
Expansions may be the key
Some scientists think that preventing CAG repeats from increasing in the brain may be key to stopping HD altogether. But no one knows how many CAGs are too many in the brain, or at what age CAG increases start to happen.
Several important genetic studies in the past few years have suggested that longer CAG repeats could help explain why brain cells die in HD. For example, people who develop HD earlier or later than expected have changes in genes that impact somatic instability of the CAG repeat in huntingtin. These genes are called “modifiers” – they modify the age at which someone starts to show symptoms of HD.
What’s interesting is that modifier genes mostly participate in the same process in the body, called mismatch repair, which is known to affect somatic instability of the CAG repeat. Very suspicious! This suggests that somatic instability of the CAG repeat is pretty important in HD.
Since somatic instability in brain cells may contribute to how these cells die, and since mismatch repair genes impact somatic instability, HD researchers are now very interested in drugs that target mismatch repair genes. Perhaps by targeting the right mismatch repair gene, we can stop somatic instability of the CAG repeat in vulnerable brain cells. The hope is that a drug which does this could slow or stop HD.
A numbers game
It turns out that we can stop somatic instability in the brain! At least we can in mice, for right now. Several pharmaceutical companies are developing HD drugs targeting mismatch repair genes and somatic instability in HD (for example, LoQus23, Rgenta, and Voyager Pharmaceuticals).
But no one really knows how long a CAG repeat must be to damage brain cells, or how early you might need to stop somatic instability in people as a treatment for HD. Recent studies in HD mice have tried to help answer these questions by looking at the impact of stopping somatic instability in HD mice with different CAG repeat lengths.
What’s helpful about HD mice is that they are born with many more CAG repeats than people with HD – because HD researchers want mice to develop symptoms of HD much faster than people do. For example, a type of mouse that models HD called “Q111” has over 100 CAG repeats. Another HD mouse model called “Q175” has about 185 CAG repeats. Both the Q111 and Q175 HD mice show symptoms of HD in less than a year.
Defining the threshold
Researchers think this threshold of about 100 CAGs may be the number of repeats needed to kill brain cells in people with HD. So what happens if you stop somatic instability in these HD mice? Do the mice get better? The answer for mice born with 185 CAG repeats, surprisingly, is no. They still develop HD, even when somatic instability is halted.
In a newly published study from the lab of Dr. Gill Bates at University College London, Q175 mice having about 185 CAG repeats were altered so that they didn’t have the mismatch repair gene MSH3. MSH3 is a high priority target for HD drug hunters since somatic instability stops altogether when MSH3 is gone.
As expected, somatic instability stopped almost completely in the brains of Q175 mice when MSH3 was eliminated. But these mice still developed features of HD, even though MSH3 was eliminated and somatic instability of the CAG repeat was halted.
What could this mean? Shouldn’t stopping somatic instability prevent the mice from developing HD? Gill’s group reasons that mice born with 185 CAG repeats already have too many repeats in the brain, so stopping expansions below 185 CAG will probably be necessary to treat HD in people.
This parallels the conclusions of a previous study which eliminated MSH3 in Q111 mice that have 100 CAG repeats, fewer than the 185 CAG repeats studied by Gill. In this other study, Dr. Vanessa Wheeler showed that Q111 mice without MSH3 have no somatic instability and have improved cellular markers of HD. So stopping somatic instability in brain cells before they reach 100 CAG repeats may be necessary for this strategy to work in people.
When should we treat HD?
This begs the question many people are asking lately: when should we treat HD? How early would a person with HD need to be treated to stop their brain cells from expanding across the threshold of 100 CAG repeats? Some brain cells appear to have 100 CAG repeats before people start to show measurable symptoms of HD. So it may be necessary to treat people even before they start to develop symptoms.
Treating people before they develop symptoms of HD poses lots of difficult questions that no one quite has the answers to yet. However, many brilliant scientists are now looking at CAG repeats directly in brains of people with HD to find answers. These insights detailing the threshold of CAG toxicity will help scientists to design better drugs and upcoming clinical trials to target somatic instability as a potential HD therapy.
A recently published collaboration between academic researchers and pharmaceutical companies was successful at detecting huntingtin in tears. The scientists were looking for a new, easy way to track Huntington’s disease (HD). If you don’t mind shedding a tear or two, they found it!
Biomarkers – biological metrics in tune with disease progression
Tracking disease progression is not only medically important to ensure patients are living a healthy life, but it’s also important for developing medicines for diseases like HD. Biological metrics that are in tune with disease progression are called biomarkers. There are different kinds of biomarkers, from images of organs, to tests of metabolism, to measurements made in body fluids.
Biomarkers are tools that researchers can use to assess how well a potential medicine is working. If a drug slows or stops the progression of a disease according to one or more biomarkers, it could mean that drug is working!
HD researchers have been working to identify biomarkers that not only track with disease progression, but also change before someone ever starts to show symptoms. Having very early HD biomarkers would allow researchers to know if a medicine is helping someone before they ever start to show disease onset. Since lots of studies are starting to indicate that the earlier we treat HD, the better off someone will be, good biomarkers will be critical for future trials.
How do we currently track HD progression?
We’ve known for a long time that HD causes brain cells to die. So imaging, like MRIs, has been used to track brain cell loss as HD progresses. However, it’s not always easy and convenient (or cheap!) to jump in an MRI machine. There are big advantages to finding easier, more accessible ways to track HD progression.
The HD research field has been moving toward identifying biomarkers in biofluids, like blood and the cerebrospinal fluid (CSF) that bathes the brain and spine. The two most notable biofluid biomarkers for HD have been neurofilament light (NfL) and the huntingtin protein (HTT) itself.
NfL has been detected in both blood and CSF. NfL is released from brain cells when they die. So as HD progresses and more brain cells are lost, amounts of NfL rise. Researchers have shown that NfL is increased in people with HD up to 24 years before they even start to show clinical symptoms! This currently makes NfL our most sensitive biomarker to track HD progression.
Getting more specific
However, NfL isn’t specific for HD. It’s released from brain cells that are dying for any reason. This could make it tricky to precisely follow HD progression if there are other reasons someone might have lost brain cells, like an illness or a hard hit to the head. To specifically track HD, researchers have turned to HTT itself.
Detecting expanded HTT in blood and CSF has been difficult. Overall, expanded HTT isn’t produced by the body in large amounts, so there isn’t much there to begin with. This means ultra-sensitive techniques must be used. HTT is also inside the cell, making it hard to get to in blood. It can be accessed more easily in CSF, but that requires a lumbar puncture. Because of this, researchers are now turning to other biofluids, like tears!
It’s just something in (both my) eyes
No one prefers to get a jab in their vein or back, if other options are available. To see if biomarkers of HD progression can be obtained more easily, researchers from the Netherlands and Germany teamed up and looked at tear fluid.
To get the tears, a small strip of special paper is placed on the lower eyelid, just touching the eye. The tears are wicked onto the paper and the strip is removed after 5 minutes.
Tears contain a surprising number of proteins – close to 1,500! Biomarkers from tears are also being explored to track other diseases, like Alzheimer’s, Parkinson’s, and multiple sclerosis. Because of this, the researchers thought tears might be a good source for HD biomarkers.
They found that amounts of expanded HTT were higher in tears from people that carry the gene for HD, whether they currently had symptoms or not. While their data were quite accurate in determining if someone carried the gene for HD, this test doesn’t appear to be sensitive enough to determine years from symptom onset or distinguish those who are experiencing symptoms from those who aren’t.
A new tool for the box
Finding new and novel ways to identify biomarkers expands our toolbox and offers easier ways for people with HD to track disease progression. Using tears to look at expanded HTT means researchers now have a new tool to examine HD in a fluid that can be collected in a non-invasive way.
Researchers will continue to advance biomarkers that are easy to collect and track with HD progression very early. Having sensitive biomarkers that can be used to measure HD before someone ever shows symptoms will set us up for success when we start testing preventative treatments. When that day arrives, we’ll be ready with tears of joy.
Long repetitive sequences of C-A-G letters in the DNA code are associated with at least 12 genetic diseases, including Huntington’s disease (HD). A group of scientists in Massachusetts, USA, have recently developed a new genetic strategy to study how CAG repeats can lead to harmful proteins being made in cells, causing cells to become unhealthy. Their findings showed that expanded CAG repeats can interfere with a process called ‘splicing’, which chops up and organises genetic message molecules before they are turned into proteins.
CAG repetition
Our DNA is a genetic code that holds instructions for making thousands of different proteins, the molecular machines that run our cells. This code is made of four building blocks or ‘bases’: C, A, G, and T. DNA is arranged like a twisted ladder with two DNA strands bound together in a helix, each made of a string of bases. The bases on one DNA strand pair with bases on the opposite DNA strand to form the ‘rungs’ of the ladder.
HD is known as a ‘CAG repeat expansion disease’. Everyone has a repetitive sequence of C-A-G DNA letters in their huntingtin gene, but people who go on to develop HD have over 36 C-A-G repeats. The number of CAG repeats can increase over time, called repeat expansion, and this seems to happen mainly in cells that get the most unhealthy in HD such as brain cells.
If we can understand exactly how a longer CAG repeat itself makes cells sick, we may be able to keep brain cells healthy and delay when HD symptoms appear. There are also other diseases caused by expansions in CAG repeats, including spinocerebellar ataxias and myotonic dystrophies. Trying to find similarities between what happens in cells affected by these other diseases may help us learn more about what goes on in HD.
Cutting scenes in the genetic script
When a cell wants to make a protein coded by a certain gene, the two DNA strands unwind and separate from each other. Cellular machinery then reads the opened-up DNA base code and makes a copy of it, called an RNA message molecule, a bit like making a photocopy of a recipe from a cookery book.
However, before any RNA message molecules are read by the next set of cellular machinery to make the corresponding protein, an essential process needs to take place. Much like editing out unnecessary scenes from a film to make a final polished version, this process involves editing the RNA message to remove all of the waffly bits of genetic code copied from DNA which aren’t actually needed to make a protein. The process of going from the unedited RNA message molecule to a shorter more succinct message is called ‘splicing’. During splicing, non-essential sections of the unedited message are cut out and the important sections that remain are pasted together to produce what is known as ‘mature’ RNA. This final mature RNA product has only the necessary instructions that the cell needs to make proteins.
Expanded CAG repeats can cause genetic plot twists
In diseases caused by expanding CAGs, the CAG repeat in the DNA is copied into the RNA message, which can cause abnormal proteins to be made. In the case of HD, an extra-long version of the huntingtin protein is made. A group of scientists led by Dr Jain in Cambridge, Massachusetts, previously found that repeat-containing RNA messages, along with the proteins made from them, combine to form toxic clumps in cells which can cause serious damage.
To find out exactly how longer CAG repeats cause the production of harmful RNA and proteins, Rachel Anderson and colleagues within the Jain team recently developed a clever new method to look in detail at the precise genetic message in RNA molecules containing large CAG repeats. Interestingly, they found that CAG repeats in RNA cause mistakes to be made during splicing of that RNA message molecule. Expanded CAG repeats in RNA cause other sections of the message molecule, sometimes far away from the CAG repeat itself, to be cut and pasted into or next to the repeat during splicing.
Here, the expanded CAG repeat can act like the opening credits of a film, into which the final scenes of the film get mistakenly inserted out of order. When this happens, the plot of the film no longer makes sense. Similarly, the final RNA message doesn’t make much sense when other sections of genetic information are inserted into the CAG repeat during splicing. This leads to the creation of many different repeat-containing mature RNAs with unexpected sequences.
The researchers found that the longer the CAG repeat in the RNA message, the more faulty splicing events that occurred. This is interesting as the CAG number in HD tracks with the age at which symptoms start and the rate at which they progress. The researchers showed that when they stopped all splicing events in cells using a chemical, repeat-containing RNA messages did not form clumps in cells and so did not cause cell toxicity.
Protein production glitches
So far, these results explain how expanded CAG repeats lead to abnormal and incorrectly spliced mature RNA messages, but what happens when these messages are read to make proteins?
Any mature RNAs that are ready to be read by cellular machinery to make a protein contain a ‘start’ signal, like a green traffic light. The researchers found that sometimes when repeat-containing RNAs are incorrectly spliced, more of these start signals are found before the repeat, causing many different proteins to be made from a single RNA message than normal. The researchers altered these start signals in the CAG repeat-containing RNAs to turn them off and found that this stopped abnormal proteins from being made.
The researchers also studied the RNA messages containing CAGs that were copied from genes associated with CAG repeat expansion diseases, including spinocerebellar ataxia and myotonic dystrophy. The researchers showed that expanded CAGs copied from these genes also caused abnormal splicing into the repeat, which again contained more protein reading start signals which may cause more abnormal proteins to be made.
What does this mean for CAG repeat expansion diseases?
Understanding how important processes in cells are impacted by long CAG repeats can help researchers piece together exactly how cells become unhealthy in CAG repeat expansion diseases and point to which processes can be targeted with therapeutics. The findings from this study add another piece to the puzzle of what happens in cells, suggesting expanded CAG repeats in RNA interfere with splicing, which can lead to damaging proteins being made.
Importantly, these experiments were performed in cell types, such as kidney cells, which are easy to grow and manage in the lab but are not most affected by HD. Therefore, these cells may not accurately reflect what causes cells to become sick in HD. A lot more work is needed looking at how expanded repeats alter RNA splicing and protein production in cell and animal models of HD. Nonetheless, targeting splicing may be a potentially exciting avenue that researchers can pursue to develop medicines for HD and other repeat expansion diseases.
