ASHuToSH PHADTE, PHD

Mentor: Anna Pluciennik, PhD

Institution: Thomas Jefferson University, Philadelphia, PA

Project Title: O xidative damage and CAG expansions in Huntington’s disease

Huntington’s disease (HD) results from an aberrant expansion of the inherited CAG repeat tract within the huntingtin (HTT) gene. This sequence can expand further in certain cell types during the lifetime of the person with HD, and many factors can influence CAG repeat instability. The brain is an oxygen rich environment, and energy production in the brain is also accompanied with the generation of reactive oxygen species (ROS), which can cause irreversible damage to the cellular DNA. ROS-mediated oxidative damage has been observed in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and HD.

Dr. Phadte’s research will investigate the effect of ROS-mediated damage on CAG repeat instability. His study will exploit the specificity of the CRISPR-Cas9 system to promote targeted oxidative damage to the CAG repeat tract of HTT to assess CAG repeat instability under oxidative stress. Using biochemical analyses, the study will also aim to identify key proteins that assemble at sites of ROS-mediated DNA damage, further enlarging our understanding of HD pathophysiology. This work has the potential to identify new therapeutic targets against HD.

PiERE RoDRiGuEz-AliAGA, PHD

Mentor: Judith Frydman, PhD

Institution: Stanford University, Palo Alto, CA

Project Title: How disease-causing mutations in the Huntingtin protein render it toxic

The risk of developing Huntington’s disease is tightly linked with the length of a specific region within the huntingtin protein

Genetic mutations can make this region longer than normal, rendering the protein toxic to neurons. The mechanism behind this length-dependent toxicity remains unknown, mainly because the huntingtin protein’s highly disordered and aggregationprone nature prevents most current experimental methods from obtaining high-resolution images of its structures. To circumvent these technical barriers, Dr. Rodriguez-Aliaga is using a new Nobel Prize-winning technology to study one huntingtin molecule at a time, a method which allows access to structural information about pathogenic and non-pathogenic huntingtin variants with unprecedented detail.

Using this approach, he has found previously unreported structural differences between the pathogenic and non-pathogenic huntingtin variants, differences which may explain how disease-causing huntingtin mutations lead to HD. He is currently studying how huntingtin’s structure is affected by chemical modifications commonly found in brains of HD patients, and other proteins and drugs known to bind huntingtin and inhibit or decrease its toxicity.

JENNiE C. lACouR Roy, PHD

Mentor: Ricardo Mouro Pinto, PhD

Institution: Massachusetts General Hospital

Harvard Medical School, Boston

Project Title: Testing of novel drugs targeting CAG repeat expansions as potential therapeutics for Huntington’s disease

There is compelling evidence that CAG repeat expansion plays an important role in Huntington’s disease age of onset and disease progression. As a result, there is an opportunity to develop therapeutics to slow or stop expansion of these repeats and modify the disease. Dr. Roy proposes the testing of a novel drug that, in preliminary studies, has slowed the CAG expansion process in a mouse model of HD, as well as in human cells in culture. This potential therapy has promising implications for the treatment and modification of HD and, potentially, other repeat expansion disorders.

SoPHiE ST-CyR, PHD

Mentor: Beverly Davidson, PhD

Institution: Children’s Hospital of Philadelphia

University of Pennsylvania

Project Title: Understanding the underlying mechanism of the heart pathology in Huntington’s disease

Heart disease is the second most common cause of mortality in Huntington’s disease and people with HD present an increased incidence of heart failure and a smaller than normal heart. Addressing this heart pathology may improve the longevity and quality of life for people with HD. Dr. St-Cyr will explore the contribution of two RNA-binding proteins (RBPs) in HD-associated cardiac pathology. RBPs are responsible for regulating the RNA splicing of hundreds of genes, a phenomenon by which different proteins are produced from the same gene and serve different functions. CELF1 is responsible for heart splicing during development, while MBNL1 does so in adulthood. She hypothesizes that an imbalance between these two RBPs is in part responsible for HD heart pathology. To test this, Dr. St-Cyr will identify all of the RNA isoforms (protein variants) abnormally expressed in the heart of an HD mouse model and determine whether increasing MBNL1 expression ameliorates heart size and contractile function.

PARTHA S. SARkAR, PHD

Institution: University of Texas Medical Branch at Galveston

Project Title: Mechanism of mitochondrial dysfunction in Huntington’s disease

Nerve tissues isolated from people with Huntington’s disease show dysfunctional mitochondria, the powerhouses of the neurons. Mitochondria play a central role in the function of neurons because of the excess and constant energy demands of neurons. The Sarkar lab discovered that the normal huntingtin protein is important for maintaining the mitochondrial DNA integrity and that abnormal huntingtin, found in HD, disrupts mitochondrial DNA integrity. Dr. Sarkar hopes to understand the precise mechanisms by which the normal huntingtin protein maintains the mitochondrial DNA and how abnormal huntingtin disrupts mitochondrial DNA integrity and its function. Understanding these processes could potentially lead to a future therapy.

CHiARA SCARAMuzziNo, PHD

Institution: Grenoble Institut des Neurosciences, France

Project Title: Impact of mutant huntingtin on retrograde axonal routing of survival signals

Huntington’s disease is characterized by the dysfunction of the neuronal circuit between two brain regions, the cortex and striatum, leading eventually to neurodegeneration. The huntingtin (HTT) protein normally facilitates the transport of BDNF, a factor fundamental for the survival of striatal neurons and to the maintenance of synapses, the structures connecting these two brain regions. When HTT is mutated, as in HD, the transport of BDNF from the cortex to the striatum is altered, thus reducing t he survival of striatal neurons. However, the mechanisms leading to the dysfunction of cortical neurons are largely unknown. To investigate these mechanisms, Dr. Scaramuzzino reconstituted an HD brain-on-a-chip, which is a micro-chamber composed of different compartments that allows her to reproduce an HD neuronal network to study the cellular features of the disease. She then identified a new signaling mechanism by which the corticostriatal synapse conveys survival signals to the cortex. She will investigate this mechanism in HD with the objective of restoring the disrupted network. This project may lead to the identifica tion of new therapeutic approaches.

SRiDHAR SElvARAJ, PHD

Mentor: Matthew Porteus, MD, PhD

Institution: Stanford University, Palo Alto, CA

Project Title: Development of a stem-cell based therapy for Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disease with no effective disease-modifying treatment. A potential therapeutic approach for HD would be to deliver protective proteins into the brain to prevent the breakdown of neurons (brain cells). Recent studies have shown that stem cell-derived neural cells have moderate therapeutic potential for HD in mouse models. Delivering protective proteins through these stem cell-derived neural cells could be a potential treatment option for humans with Huntington’s as well. In this study, Dr. Selvaraj will test the therapeutic potential of this approach for the delivery of four different protective proteins into HD mouse models. The study will provide a proof-of-concept platform for stem cell-based delivery of therapeutic proteins as a novel treatment approach for HD.

JoAN STEFFAN, PHD

Institution: University of California, Irvine

Project Title: Identification of Huntingtin-dependent cellular trash collection pathways

Dr. Steffan is investigating the normal function of the huntingtin protein in the cell’s trash collection system, a process called autophagy . Huntingtin is involved in helping to target the trash to be transported to a part of the cell, called the lysosome , where it is degraded and recycled. A small protein called ubiquitin carries the tagged trash to its destination. Dr. Steffan is examining the direct interaction between huntingtin and ubiquitin, defining the kinds of trash huntingtin scaffolds, and explor ing how this process may be impaired by the HD mutation. Through this approach, she aims to find therapies that may improve mutant huntingtin’s function and slow the progression of the disease.

ANDREw. F. TEiCH, MD, PHD

Institution: New York Brain Bank

Columbia University Irving Medical Center, NY

Project Title: Human tissue banking for the Huntington’s disease research community

The New York Brain Bank (NYBB) of Columbia University currently makes available to researchers over 1,000 carefully characterized Huntington’s disease brains as well as other human tissues. A state-of-the-art barcode inventory system, implemented by pathologist and NYBB founder Dr. Jean Paul Vonsattel, tracks the storage and disbursement of all tissue samples.

Dr. Teich aims to broaden the autopsy service to provide researchers with a greater variety of tissues, as well as scanned slides, from individuals who have died with the expanded version of the Huntington’s gene and have authorized banking of their tissue. These enriched resources will offer the research community new insights into the disease mechanisms of HD and pave the way towards better treatments and therapies for people living with HD.

RAy TRuANT, PHD

Institution: McMaster University, Hamilton, Ontario, Canada

Project Title: Imaging huntingtin at DNA sites at the atomic level

Huntington’s disease affects the way neurons (brain cells) respond to DNA damage, interfering with DNA repair and potentially triggering the events that ultimately lead to the disease. In 2017, the Truant lab visualized the recruitment of the huntingtin protein to sites of DNA damage, but huntingtin has no obvious regions known to bind DNA. So what allows huntingtin to interact with DNA, particularly at sites of DNA damage, and how might this interaction initiate HD ? It appears likely that huntingtin requires another protein, called Hap40, to bind DNA. Dr. Truant will visualize how the huntingtin/Hap40 complex directly binds to DNA and to polyADP-ribose (PAR), an important signal molecule for DNA repair that has been identified in many brain diseases. He will test various DNA shapes, as well as various types of DNA damage, comparing unexpanded and expanded huntingtin to see how the disease mutation affects the ability to bind DNA. This work will help the field understand when and how the huntingtin protein is recognizing damaged DNA and possibly how it is driving the DNA damage aspect of HD.

ANDREw S. yoo, PHD

Institution: Washington University School of Medicine, St. Louis, MO

Project Title: Increasing resilience against neurodegeneration in Huntington’s disease patient-derived neurons

Huntington’s disease is characterized by massive death of striatal medium spiny neurons (MSNs). Dr. Yoo previously found that reprogramming skin fibroblasts of people with HD to MSNs (HD-MSNs) showed adult onset pathologies, including the formation of huntingtin aggregates and cell death. Building on this work, he recently identified RCAN1 as a gene whose reduced function rescued HD-MSNs from neuronal death. However, it remains unclear how RCAN1 operates at the molecular level to promote HD-MSN degeneration. In this project, Dr. Yoo will investigate the molecular events that emerge as he reduces the function of RCAN1 and enhances HD-MSNs’ resilience in the face of neurotoxicity caused by mutant huntingtin. This work will deepen our understanding of fundamental changes in the cellular state that underlie the increased survival of patientderived neurons. He also hopes to infer strategies to keep neurons of people with HD from degenerating.

This is the Golden Age of HD research. The number of papers being published, the number of people that are now migrating to the HD field, the amount of resources, the number of companies that are finding this a desirable space - it’s unprecedented. We can make a difference in this disease. We will continue to move the ball forward, and we will not stop until we succeed.

George Yohrling, PhD Senior Director, Global Program Leader, Neuroscience Bristol Myers Squibb