Grants & Fellowships
HDF is passionate about finding and funding the most promising, creative and paradigm-changing research.
“ HDF creates a culture of creativity, excellence, collaboration, and a sense of community and shared purpose which helps to attract generations of scientists to join and stay in the field. Looking back on the decades of my scientific career, it all started with my very first grant from the Foundation.”
X. William Yang, MD, PhD
David Geffen School of Medicine at UCLA
HDF is passionate about finding and funding the most promising, creative and paradigm-changing research.
“ The Huntington’s Disease Foundation creates a culture of creativity, excellence, collaboration, and a sense of community and shared purpose which helps to attract generations of scientists to join and stay in the field. Looking back on the decades of my scientific career, it all started with my very first grant from the Foundation.”
X. William Yang, MD, PhD
David Geffen School of Medicine at UCLA
HDF grants enable many researchers to receive major long-term funding from other sources, including the National Institutes of Health. Postdoctoral fellowships are awarded to promising early career researchers and are intended to support and cultivate their interest in Huntington’s disease. The Huntington’s Disease Career Advancement Grant (HD-CAG) is an accelerator program for senior postdoctoral researchers.
The following is a list of currently funded HDF researchers.
Grants
Sonja Blumenstock, PhD
Project Title: Restoring healthy communication between brain cells in Huntington’s disease
Dr. Blumenstock will study how a special group of brain cells called VIP interneurons helps the brain stay flexible and learn new movements. In Huntington’s disease, these helpful cells are much less active, and the brain’s movement pathways become weak and unstable. She will examine whether gently boosting the activity of these helper cells can strengthen the connections between brain cells and make movement signals steadier. She will also test whether specific existing medicines can create similar improvements. Dr. Blumenstock aims to uncover how to repair the brain circuits that guide movement. By restoring clearer communication between key groups of brain cells, the work may help pave the way for new treatments that improve motor function in people with HD.
Sonja Blumenstock, PhD
University of California, San Diego
Verónica Inés Brito, PhD
Project Title: A DNA repair activity measurement to evaluate emerging HD therapies
Neurons are highly active and constantly transcribing genes like Huntingtin. During this nonstop activity, the DNA can sometimes develop tiny errors, so neurons rely on DNA‑repair systems that are always at work fixing them. Dr. Brito studies how cells correct tiny errors in one specific part of the Huntingtin gene, where the repair process itself can sometimes make a small DNA section grow longer over time, a process called somatic instability. These repair events happen far more often than the actual DNA expansions, so measuring them provides an early and sensitive signal of what is happening inside the cell.
Dr. Brito and her team created a test to detect and map where this repair activity occurs in brain and blood cells. They will use it to learn which cellular repair factors and pathways are responsible, how different treatments may change this repair activity, and whether the test can reveal an early sign that a treatment is working. By focusing directly on the repair activity that drives somatic instability, this approach offers a precise and timely way to understand the disease process and guide new therapies.
Verónica Inés Brito, PhD
University of Barcelona, Spain
Katherine Croce, PhD
Project Title: Examining how aggregate clearance improves HD brain cells
To keep cells healthy, there is a system that removes garbage from the cell’s environment. Specifically, in cells of a Huntington’s disease brain, there is a particular type of garbage, called aggregates, that builds up and causes problems. Dr. Croce’s work focuses on a protein called Alfy that can find these aggregates and remove this garbage from the cell. Her postdoctoral research used HD mice to determine that after the HD mice are symptomatic, an increase of Alfy in brain cells leads to fewer aggregates, and in turn, slows progression of the disease. Based on that data, Dr. Croce will use the brain tissue from these HD mice to determine how cells specifically react when the aggregates/garbage are present or not, as well as how the cells change with more Alfy to remove the garbage.
Katherine Croce, PhD
Columbia University Medical Center, New York
Amit Laxmikant Deshmukh, PhD
Project Title: Disrupting FAN1 and MLH1 interaction to stop Huntington’s disease features
In Huntington’s disease, CAG repeats in the huntingtin gene increase in length over time (known as somatic expansion). This ongoing mutation occurs in the brain and leads to earlier onset and faster progression of the disease. Stopping or reversing these expansion mutations could provide a new approach to treating HD. The proteins FAN1 and MLH1 regulate these mutations: FAN1 helps suppress CAG expansions, while MLH1 promotes it. Dr. Deshmukh’s research has revealed that these proteins can work together, and that disrupting their interaction can stop expansions in brains of mice that model HD. He hypothesizes that disrupting the interaction between FAN1 and MLH1 could help prevent somatic expansion and improve cellular features of HD, like protein clumping and inflammation. The results of this study may indicate whether targeting the FAN1-MLH1 interaction could potentially serve as a safe therapeutic for HD.
Amit Laxmikant Deshmukh, PhD
The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada
Steven Goldman, MD, PhD
Project Title: Establishing how healthy brain cells can replace diseased cells in HD
Glial cells are the support cells of the brain that enable neurons to function well. Glial cells function poorly in Huntington’s disease, contributing significantly to the decline of function in people with HD. Yet these diseased glial cells may be replaced by healthy cells that are transplanted directly into the brain. This approach results in increased function and longer survival in mice with HD, and should also work in people with HD. The process of cell replacement involves competition between the transplanted and resident cells, regulated by molecules on the surfaces of the healthy and diseased cells. This interaction allows the replacement of the diseased HD cells. Dr. Goldman aims to identify these molecules and test them in human glial cells to see which might be used to improve the competitive replacement of HD cells by healthy glia.
Steven Goldman, MD, PhD
University of Rochester, NY
Rachel J. Harding, PhD
Institution: University of Toronto, Ontario, Canada
Project Title: Developing chemical tools to investigate HAP40, the partner of the Huntington’s disease protein
2024 Nancy S. Wexler Young Investigator Prize Recipient
The Huntington’s disease protein, huntingtin, has a partner protein called HAP40. Huntingtin wraps around HAP40, positioning HAP40 like a burger in a huntingtin bun, and making a very stable complex of these two molecules. There is a growing body of evidence that huntingtin bound to HAP40 is an important protein assembly in the cell. The levels of the two proteins track together, they are coevolved, and removing one mirrors the results of removing the other. Dr. Harding with her team have identified and developed tight binding tool molecules which stick specifically to HAP40. She has validated these tools with many different approaches and now seeks to modify them to make degraders – tools that lower levels of a specific protein, in this case HAP40. She will design, make, and characterize these degrader tools with the view to deploy them in different HD model systems to further pinpoint the role of HAP40 in HD biology.
Rachel J. Harding, PhD
University of Toronto, Ontario, Canada
Michael Hayden, PhD, FRCP(C), FRSC
Institution: University of British Columbia, Vancouver, Canada
Project Title: Investigating whether large CAG repeat expansions in the brain cause early onset of Huntington’s disease in patients with DNA sequence changes in the HD gene
In brains of people with Huntington’s disease, the DNA sequence of the CAG repeat expands to become very long in neurons that die earliest in the disease. It was recently shown that small changes in the DNA sequence of the CAG repeat can also affect how early someone develops HD, sometimes by more than a decade. One explanation for how these small changes in the DNA sequence of the CAG repeat cause early onset of HD is that they may increase the number of long expanded CAG repeats in neurons that die earliest in HD, worsening the disease. This proposal will investigate one important DNA sequence change in the CAG repeat in brain tissues from people who develop HD earlier than others. Investigating increased CAG repeat expansion and other potential disease mechanisms in brain tissue from people with HD with this change in the CAG repeat will clarify our understanding of how HD develops and how to develop effective therapies.
Michael Hayden, PhD, FRCP(C), FRSC
University of British Columbia, Vancouver, Canada
David Housman, PhD
Institution: Massachusetts Institute of Technology, Cambridge
Project Title: Targeting DNA repair to reduce repeat expansion in Huntington’s disease
2010 Leslie Gehry Prize for Innovation in Science
Dr. Housman and his team aim to develop a new therapeutic approach for Huntington’s disease, which currently has no effective disease-modifying treatments. HD is caused by an expanded DNA repeat that can grow further in affected brain cells over time, contributing to neurological dysfunction and disease progression. Building on genetic studies in people with HD and work in HD model systems, the team will test a targeted strategy to increase levels of a DNA repair enzyme that helps stabilize repetitive DNA and limit further repeat growth. The goal is to boost this enzyme so that brain cells accumulate fewer harmful repeat changes, which may slow the underlying disease process. If successful, this work could support the development of therapies that preserve brain function and improve quality of life for people living with HD, and may provide a foundation for related repeat expansion disorders.
David Housman, PhD
Massachusetts Institute of Technology, Cambridge
Icnelia Huerta Ocampo, MD, PhD
Project Title: Assessing the therapeutic impact of gene-silencing strategies across brain cell types in Huntington’s disease
Gene lowering therapies are a promising approach for Huntington’s disease, but researchers still need to understand how these treatments affect different types of brain cells and regions. Dr. Huerta Ocampo will focus on uncovering how gene-silencing treatments change the brain at the level of individual cells. She is using advanced tools that allow thousands of single brain cells to be studied at once. She is testing therapies designed to lower harmful gene activity and examining how this influences gene function, cell health, and the buildup of disease-related protein clumps in specific brain areas. She will also measure changes in the genetic instability that contributes to disease progression, helping to connect molecular changes with improvements seen in brain tissue.
Icnelia Huerta Ocampo, MD, PhD
The Children’s Hospital of Philadelphia, PA
Chris Kay, PhD
Institution: University of British Columbia, Vancouver, Canada
Project Title: Investigating whether large CAG repeat expansions in the brain cause early onset of Huntington’s disease in patients with DNA sequence changes in the HD gene
In brains of people with Huntington’s disease, the DNA sequence of the CAG repeat expands to become very long in neurons that die earliest in the disease. It was recently shown that small changes in the DNA sequence of the CAG repeat can also affect how early someone develops HD, sometimes by more than a decade. One explanation for how these small changes in the DNA sequence of the CAG repeat cause early onset of HD is that they may increase the number of long expanded CAG repeats in neurons that die earliest in HD, worsening the disease. This proposal will investigate one important DNA sequence change in the CAG repeat in brain tissues from people who develop HD earlier than others. Investigating increased CAG repeat expansion and other potential disease mechanisms in brain tissue from people with HD with this change in the CAG repeat will clarify our understanding of how HD develops and how to develop effective therapies.
Chris Kay, PhD
University of British Columbia, Vancouver, Canada
Kimberly Kegel-Gleason, PhD
Project Title: Fat metabolism in Huntington’s disease
Huntington’s disease brains must rely on alternative energy sources besides glucose, like fats. However, metabolism of fats creates a reactive oxygen species which can damage cells. While researchers know that neurons in HD mouse brains accumulate organelles called lipid droplets that stockpile fats, it is not known how neurons metabolize these fats. Defining how HD impacts neuronal fat storage and metabolism could help identify potential therapeutic targets to improve brain cell health. Dr. Kegel-Gleason will use a novel chemical compound capable of tracking which cells use fats to create energy. She will label brain cells in wild-type and knock-in HD Q140 mice to determine which kinds of cells (neurons or glia) consume fats to survive. Finally, she will test the same compound in human neurons derived from stem cells.
Kimberly Kegel-Gleason, PhD
Massachusetts General Hospital, Harvard Medical School, Boston
Seongwon Lee, PhD
Institution: Mercer University, Macon, GA
Project Title: Exploring how TET1 helps protect the brain in Huntington’s disease
Aging brings increased health challenges, notably in the brain, where conditions like Huntington’s disease cause gradual breakdown of brain cells. Drs. Oh and Lee aim to understand the reasons behind this process. Using a unique method, they convert skin cells into brain cells for comparison between younger and older individuals with HD. A molecule called TET1 is linked to cell communication but its impact on HD is unknown. Drs. Oh and Lee aim to explore TET1’s role in HD-induced brain cell damage by reducing TET1 levels in cells from younger individuals with HD. They will also intentionally alter levels of TET1 in cells from younger individuals with HD to measure TET1’s impact on HD cellular features. This research will help to understand why brain cells break down in HD and find new ways to treat it.
Seongwon Lee, PhD
Mercer University, Macon, GA
Christian Neri, PhD
Project Title: Extracellular vesicles as a source of new-generation biomarkers for Huntington’s disease
Extracellular vesicles (EV) clear out waste within cells and promote communication between cells and organs. They are particularly important for maintaining tissue health. EVs have great therapeutic potential in the fight against neurodegenerative diseases as they can provide targets and biomarkers for early intervention. However, these vesicles differ from each other, making it difficult to know the role of a specific EV in specific neurons. Dr. Neri will use cutting-edge technologies to study the composition and role of small EVs in neuronal networks affected by Huntington’s disease and define their biomarker potential.
Christian Neri, PhD
Sorbonne University, Paris, France
Chris Ng, PhD
Institution: Massachusetts Institute of Technology, Cambridge
Project Title: Targeting DNA repair to reduce repeat expansion in Huntington’s disease
Dr. Housman and his team aim to develop a new therapeutic approach for Huntington’s disease, which currently has no effective disease-modifying treatments. HD is caused by an expanded DNA repeat that can grow further in affected brain cells over time, contributing to neurological dysfunction and disease progression. Building on genetic studies in people with HD and work in HD model systems, the team will test a targeted strategy to increase levels of a DNA repair enzyme that helps stabilize repetitive DNA and limit further repeat growth. The goal is to boost this enzyme so that brain cells accumulate fewer harmful repeat changes, which may slow the underlying disease process. If successful, this work could support the development of therapies that preserve brain function and improve quality of life for people living with HD, and may provide a foundation for related repeat expansion disorders.
Chris Ng, PhD
Massachusetts Institute of Technology, Cambridge
Youngmi Oh, PhD
Institution: Mercer University, Macon, GA
Project Title: Exploring how TET1 helps protect the brain in Huntington’s disease
Aging brings increased health challenges, notably in the brain, where conditions like Huntington’s disease cause gradual breakdown of brain cells. Drs. Oh and Lee aim to understand the reasons behind this process. Using a unique method, they convert skin cells into brain cells for comparison between younger and older individuals with HD. A molecule called TET1 is linked to cell communication but its impact on HD is unknown. Drs. Oh and Lee aim to explore TET1’s role in HD-induced brain cell damage by reducing TET1 levels in cells from younger individuals with HD. They will also intentionally alter levels of TET1 in cells from younger individuals with HD to measure TET1’s impact on HD cellular features. This research will help to understand why brain cells break down in HD and find new ways to treat it.
Youngmi Oh, PhD
Mercer University, Macon, GA
Anna Pluciennik, PhD
Project Title: Enhancing the function of FAN1 enzyme for Huntington’s disease therapeutics
Dr. Pluciennik seeks to understand the mechanisms by which certain repeating stretches of DNA in brain cells gradually grow longer (expand) over an individual’s lifetime, ultimately contributing to the development and progression of Huntington’s disease. Her recent research has demonstrated that the DNA repair enzyme FAN1 works in cooperation with the protein PCNA to suppress these harmful DNA expansions. Building on this discovery, Dr. Pluciennik proposes that strengthening the interaction between these two proteins may increase the effectiveness of this naturally protective system, thereby reducing repeat expansion and potentially slowing the progression of the disease. This line of investigation may pave the way for novel therapeutic strategies for HD.
Anna Pluciennik, PhD
Thomas Jefferson University, Philadelphia, PA
Lynn A. Raymond, PhD, MD
Project Title: Role of altered inhibitory drive in brain pathology of Huntington’s disease
Dr. Raymond’s project focuses on a small group of brain cells (“PV interneurons”) that act like brakes, stopping other cells from becoming too active. In Huntington’s disease, these brake cells seem to work poorly, which may affect normal patterns of brain activity and contribute to problems with information processing in the brain and consequently movement and learning. Dr. Raymond will compare how these cells grow and mature from childhood to adulthood, and how they function in the brains of mouse models of HD and their healthy littermates. She will then test two ways to strengthen these brake cells: (1) by gently increasing their activity during early life, and (2) boosting their activity later using medicines that help these cells do their job more reliably.
Lynn A. Raymond, PhD, MD
University of British Columbia, Canada
Charlene Smith, PhD
Project Title: Defining molecular drivers of mitochondrial dysfunction in Huntington’s disease
In Huntington’s disease, mitochondria—the cell’s energy producers—do not function properly, contributing to neuronal dysfunction and degeneration. Dr. Smith and her colleagues previously discovered abnormally enlarged RNA granules within HD mitochondria. These granules carry genetic instructions needed to make proteins essential for mitochondrial health. She now will investigate how enlarged mitochondrial RNA granules disrupt mitochondrial structure, composition, and energy function, and how these changes impair communication between neurons at synapses. The study will also examine why these granules become enlarged in HD, including whether defects in mitochondrial protein import contribute to this process. Using patient-derived stem cells, the research will model affected neurons in both 2D and 3D systems, with a particular focus on striatal neurons—the cell type most vulnerable in HD. By defining the mechanisms linking mitochondrial dysfunction to neuronal communication, this work aims to identify new pathways that may be targeted to slow or prevent disease progression.
Charlene Smith, PhD
University of California, Irvine
Eric T. Wang, PhD
Institution: University of Florida, Gainesville
Project Title: What causes the Huntingtin protein exon 1 fragment to form, and do different CAG repeat sequence variants form it more readily?
Over the years, it has been discovered that the Huntingtin protein with expanded CAG repeats can exist in a non-canonical form – a version containing just the beginning portion of the full-length human protein. This shortened form of the protein is extremely toxic, but it is still not well understood how it forms. One hypothesis for how it forms is that the RNA encoding huntingtin protein is actually mis-processed, rather than the full length huntingtin protein being cleaved to yield this product. Dr. Wang is interested in defining whether specific huntingtin RNA sequences and cellular factors control mis-processing of the huntingtin RNA itself. Better understanding the factors that influence formation of the shortened huntingtin protein could identify therapeutic targets and also explain why certain interruptions in the CAG repeat sequence might cause earlier or later age of symptom onset.
Eric T. Wang, PhD
Institution: University of Florida, Gainesville
Postdoctoral Fellowships
Swati Balakrishnan, PhD
Institution: University of Toronto, Ontario, Canada
Project Title: Investigating the role of a protein variant in damage to genetic material
The huntingtin gene contains repeating ‘CAG’ DNA letters. Too many CAG repeats causes Huntington’s disease, and as certain cells age they can erroneously add more repeats to the gene. This type of mutation is usually fixed by many molecular machines called DNA repair proteins. One of these proteins is RPA, which binds DNA and signals other repair machines to find and correct damage. RPA has another version called Alt-RPA, which works against RPA. Alt-RPA is seen at high levels in HD brains compared to healthy ones and contributes to expansion of CAG repeats, but little is known about how it works or how to block its action. Dr. Balakrishnan aims to visualize Alt-RPA using cutting-edge microscopes, discover the kind of DNA it interacts with and design molecules to prevent Alt-RPA from working. Her study will determine the function of this crucial DNA repair protein and help discover HD therapies.
Swati Balakrishnan, PhD
University of Toronto, Ontario, Canada
Ivana Vujkovic Bukvin, PhD
Mentor: Judith Frydman, PhD
Institution: Stanford University, CA
Project Title: Mapping the shape of pathogenic huntingtin during its synthesis on the ribosome
Dr. Bukvin wants to study a protein called huntingtin, which is made inside our cells on a machine called a ribosome. This protein is important because changes in its shape might lead to Huntington’s disease. She and her team in the Frydman laboratory are curious if the shape of huntingtin changes while it is being made by the ribosome and if this change affects how it works and interacts with other proteins in our cells. They are also interested in seeing how huntingtin interacts with chaperone proteins, which help proteins acquire their correct shape in cells. To do this, Dr. Bukvin will use different colored dyes to mark huntingtin proteins while they are being made by the ribosome. The color footprints will help her describe the different huntingtin proteins shapes the ribosome creates in great detail and identify if any of these shapes are harmful to cells.
Ivana Vujkovic Bukvin, PhD
Stanford University, CA
Vanessa H. Casha, PhD
Institution: University of California, Los Angeles
Project Title: Uncovering new therapies for Huntington’s disease by examining subcompartments in brain cells
2025 Nancy S. Wexler Young Investigator Prize Recipient
Huntington’s disease is caused by mutations that produce mutant Huntingtin (mHTT) protein, but how and why this mHTT has such a devastating effect on the brain is still not fully understood. Dr. Casha seeks to pin this down by zeroing in on the brain cells that are most affected in HD: striatal astrocytes and neurons. She hypothesizes that on and within the surface of these cells, and within their nuclei, key proteins exist that are the molecular mediators of the disease. By using novel methods developed in the Khakh lab, Dr. Casha aims to identify such proteins to create a map of which proteins are affected within specific subcompartments of the cells. This map can help us better understand the specific proteins responsible for dysfunction and recovery in HD and, importantly, this information can be used to develop and test new therapies.
Vanessa H. Casha, PhD
University of California, Los Angeles
Francisco Garcia, PhD
Institution: Massachusetts Institute of Technology, Cambridge
Project Title: Viruses targeting blood vessels in the brain as a therapeutic strategy for Huntington’s disease
In the brain, blood vessels are not only important for shuttling all essential nutrients for normal function but also create a protective barrier. In Huntington’s disease, brain blood vessels are “leaky” and can accelerate the disease process. Dr. Garcia’s work will focus on targeting the blood vessels themselves to correct their disease pathology. By using specialized viruses that can selectively enter the cells of these blood vessels, he will be able to specifically determine if repairing the blood vessels in the brain is a viable therapeutic approach. To do so, he will utilize mouse models of HD and perform a variety of experiments to assess therapeutic benefit. In doing so, he will not only assess the feasibility of targeting blood vessels in the brain but also understand the biological processes that this enables.
Francisco Garcia, PhD
Massachusetts Institute of Technology, Cambridge
Christian Makhoul, PhD
Mentor: Danny Hatters, PhD
Institution: University of Melbourne, Australia
Project Title: Stuck in a loop: how mutant huntingtin could be exacerbating its own mutation
The aim of this research project is to uncover cell processes that have become compromised in the context of Huntington’s disease. Proteins make up a core component of the cell composition and interact with each other to tightly regulate processes that are crucial for cell and organ health. In Huntington’s disease, specialized regions of the brain are dramatically affected due to a mutation of a single gene that encodes the huntingtin protein. Using specialized techniques that monitor how protein interactions are changed, it was uncovered that huntingtin may be interacting with other cell proteins to exacerbate its own mutation. This is an exciting discovery that has not been previously documented. This project aims to further explore the details of this interaction to understand how it can be regulated to mitigate disease.
Christian Makhoul, PhD
University of Melbourne, Australia
Won-Seok Lee, PhD
Institution: Eli and Edythe L. Broad Institute of MIT and Harvard, Boston, MA
Project Title: How accumulation of the Huntington’s disease protein harms patients’ brain cells
Dr. Lee aims to discover why brain cells die in Huntington’s disease. He recently found that when a small stretch of repeated DNA in the HD gene grows too long, those brain cells start forming sticky clumps of huntingtin protein inside the nuclei, their control centers. These clumps may disrupt normal cell activities—like turning the correct genes on and off, and keeping DNA neatly folded and organized. Dr. Lee wants to understand how and when these clumps form, which other proteins get trapped inside the clumps, and how this makes brain cells lose control of their vital functions. By uncovering how these clumps make brain cells sick, Dr. Lee hopes to reveal clues that could help protect cells and lead to new ideas for treatments for HD.
Won-Seok Lee, PhD
Eli and Edythe L. Broad Institute of MIT and Harvard, Boston, MA
Marta Prieto García, PhD
Mentor: Frederic Saudou, PhD
Institution: Floralis UGA Filiale, France
Project Title: Reducing toxic stress to protect the brain in Huntington’s disease
Our brain cells use small carriers, called vesicles, to move molecules from one place to another. To travel long distances inside nerve cells, these vesicles need energy, which they can make themselves using special enzymes. Recently it was found that vesicles also carry another helpful enzyme called G6PD. When cells face oxidative stress—a condition where harmful molecules are produced, G6PD accumulates on the vesicles which seems to help clean up the damaging molecules and keep the cells alive. This is important because people with Huntington’s disease have higher levels of these harmful molecules. Dr. Prieto Garcia will look at ways to make G6PD work better on vesicles so it can help brain cells clean up harmful molecules, stay healthy, and survive longer. This may protect people with HD and could lead to new treatments for brain disorders in which oxidative stress plays a major role.
Marta Prieto García, PhD
Floralis UGA Filiale, France
Colby Samstag, PhD
Institution: University of Washington School of Medicine, Seattle
Project Title: Using emerging scientific tools to test a new idea about the Huntington’s disease gene
Huntington’s disease is caused by a spelling mistake in the DNA instructions for making the Huntingtin protein. This mistake is like accidentally copying and pasting the same three-letter word over and over again in a sentence. Although this gene was discovered over 30 years ago, researchers still don’t fully understand how this repetitive mistake causes disease or why it primarily affects certain brain cells. Recent research suggests that this DNA error may also produce instructions that cause cells to make a particularly toxic protein called HTT1a, in addition to problems with the normal Huntingtin protein. However, much of what we know about HTT1a comes from animal models, and it is not clear whether the same processes occur in human disease. Dr. Samstag is developing new technologies to detect HTT1a and measure its effects in human tissue. Using brain tissue generously donated by patients after death, he is now applying these tools to determine whether HTT1a contributes to disease in people and to identify new targets for therapeutic development.
Colby Samstag, PhD
University of Washington School of Medicine, Seattle
Shota Shibata, MD, PhD
Institution: Massachusetts General Hospital, Harvard Medical School, Boston
Project Title: Developing a novel approach to monitoring Huntington’s disease progression
Huntington’s disease is caused by unstable CAG repeats, which expand in some cells over time. These changes, called somatic instability (SI), affect how the disease progresses. Measuring SI is difficult because current methods are biased and require invasive brain tissue samples. Dr. Shibata is working to develop a new, precise way to measure SI using advanced DNA labeling and sequencing methods. To make testing easier, he will focus on collecting non-invasive samples from sources like cells in the nose or blood. By comparing these samples, he aims to create a reliable method to measure SI without invasive procedures. The goal is to use SI as a marker for tracking HD progression and testing new treatments. This research could improve care for HD patients and others with similar genetic conditions, helping us find better treatments and move closer to a cure.
Shota Shibata, MD, PhD
Massachusetts General Hospital, Harvard Medical School, Boston
Xiaojing Sui, PhD
Mentor: Richard Morimoto, PhD
Institution: Northwestern University, Evanston, IL
Project Title: Watching how protein clearance becomes faulty with aging in Huntington’s disease
The health and function of our cells rely on the recycling machine, known as the proteasome, to clean up old and damaged proteins. However, with Huntington’s disease, the proteasome cannot do its job properly and it gets worse as patients get older. Dr. Sui aims to understand exactly how this happens. She has developed a high-throughput and very sensitive approach, which allows her to watch how the proteasome changes its shape in HD in unprecedented detail. Using this method in worms that model HD, she has found that the proteasome is getting jammed up with too much garbage to clean when animals get old. She is now studying how the HD mutation makes the proteasome slow down even more at the molecular level. This helps her understand why HD gets worse over time. And if she can figure out how to fix this problem with the proteasome, it might lead to new treatments for HD.
Xiaojing Sui, PhD
Northwestern University, Evanston, IL
Takeshi Uenaka, MD, PhD
Institution: Stanford University School of Medicine, CA
Project Title: Understanding how the brain’s immune cells can reduce huntingtin clumping within neurons in human stem cell models
In neurodegenerative diseases, including Huntington’s disease, abnormal proteins build up in the brain, forming clumps that cause harm. Some scientists believe that stopping this protein buildup could help treat these diseases. Interestingly, microglia, the brain’s immune cells, may play a role in controlling these protein clumps. Dr. Uenaka’s research has shown that microglia can remove harmful protein buildup from within brain cells. He now aims to explore how microglia manage protein accumulation in other cells, with the goal of finding new ways to slow or stop the progression of these diseases.
Takeshi Uenaka, MD, PhD
Stanford University School of Medicine, CA
Huntington’s Disease Career Advancement Grants (HD-CAG)
Chris Kay, PhD
Mentor: Michael Hayden, PhD, FRCP(C), FRSC
University of British Columbia, Vancouver, Canada
Devon Pendlebury, PhD
Mentor: Leslie M. Thompson, PhD
University of California, Irvine
Piere Rodriguez-Aliaga, PhD
Mentor: Judith Frydman, PhD
Stanford University, Palo Alto, CA
Sonia Vazquez-Sanchez, PhD
Mentor: Don Cleveland, PhD
Institution: University of California at San Diego
Shota Shibata, MD, PhD
Mentor: Ricardo Mouro Pinto, PhD
Massachusetts General Hospital
Harvard Medical School, Boston