HDF RESEARCH GRANTS HyESEuNG lEE, PHD

Mentor: Myriam Heiman, PhD

Institution: Picower Institute for Learning and Memory

Massachusetts Institute of Technology, Cambridge

Project Title: Therapeutic targeting of Huntington’s disease with key regulators of innate immunity

In Huntington’s disease, mutant huntingtin protein ( m HTT) is expressed everywhere in the body. However, specific types of cells within the brain’s cortex and basal ganglia are more likely to die than other types of cells or than cells elsewhere in t he body. This circumstance highlights the importance of understanding how each of these different types of cells respond to mHTT. Dr. Lee and colleagues recently discovered a cell type-specific activation of innate immune signaling that they believe leads to enhanced neuronal vulnerability in HD. They hope to identify key genes that activate this immune signaling and test their therapeutic potential in Huntington’s disease.

RyAN liM, PHD

Institution: University of California, Irvine

Project Title: Interactions between metabolism, gene expression, and gender in Huntington’s disease

Changes in metabolism—that is, in how the cell generates energy—can affect gene expression. This interaction has been described for many disorders. However, it is unclear just how these two processes interact during disease.

Dr. Lim proposes that this interaction in the brain plays a central role in HD and that gender differences in gene expression and metabolism may result in sex-specific disease effects, a topic that has been little studied. This project investigates the inte rface between metabolism and gene expression to further understand how HD arises and progresses while exploring the possible role of gender.

JAMES MACkAy, PHD

Mentor: Lynn A. Raymond, MD, PhD, FRCPC

Institution: University of British Columbia, Vancouver, Canada

Project Title: Assessing early changes in sensory-related brain activity in Huntington’s disease

People with Huntington’s disease typically show disordered cognition and movement in middle age due to the degeneration of specific brain circuits. However, underlying HD processes begin earlier and are not completely understood. Dr. Mackay and his colleagues’ research has shown that altered sensory signals (evoked by touch, sound, etc.) spread extensively across the brain surface in HD mice and suspect that these altered brain signals could be seen with available neuro-imaging techniques in humans with HD as well. His current project aims to determine how these signals evolve with disease progression in order to validate their potential as markers of disease (biomarkers). Dr. Mackay hypothesizes that changes in the excitatory synapses (structures that mediate communication between brain cells) underlie these altered brain signals and that these changes confer vulnerability to brain cell degeneration. He aims to characterize these brain circuit changes and determine whether correcting them with drugs early in the illness can prevent neurodegeneration.

SRivATHSA MAGADi, PHD

Mentor: Walker Jackson, PhD

Institution: Linköping University, Sweden

Project Title: Modulate immune cells of the brain to alleviate Huntington’s disease

Microglia, the immune cells of the brain, have both neuroprotective and neurotoxic potential. A fine balance between these opposing capacities is disrupted in brain diseases. Dr. Magadi and colleagues found that the brains of people with Huntington’s disease produce a specific form of a ribosomal protein, Rps24, which the brains of individuals without Huntington’s do not. They hypothesize that this form of the protein is used by microglia to help the brain fight the disease. To test this hypothesis, Dr. Magadi will use cells in a dish to understand the molecular purpose of this version of the Rps24 protein. He will also use genetically engineered mouse models that enable researchers to control the production of the potentially beneficial version of Rps24 in the brain. If this form of the Rps24 protein can alter the course of the disease in mouse models , such findings can potentially be used to tailor drugs that will elicit similar effects in humans.

zACHARiAH l. MClEAN, PHD

Mentor: James F. Gusella, PhD

Institution: Massachusetts General Hospital

Harvard University, Boston

Project Title: Identifying modifiers of Huntington’s disease CAG repeat expansion and its consequent disruption of messenger RNA

The inherited expanded CAG repeat that underlies Huntington’s disease expands over time in neurons, at a rate that is modified by selected genes normally involved in repairing DNA damage. Increasing repeat length also causes HD gene (HTT) messenger RNA (mRNA) to end abruptly, which may contribute to toxicity in neurons.

Dr. McLean will construct a novel tool for selecting cultured cells with expanded or contracted CAG repeats. This tool is a system known as a reporter and is based on CAG repeat length-dependent disruption of HTT mRNA observed in patients. The reporter will be used to quantify the CAG repeat expansion rate of different patient derived alleles, which have the same length of uninterrupted CAG repeats but different DNA bases on either side. Additionally, he will undertake a screen to identify genes that modify CAG repeat instability or the disruption of HTT mRNA. Novel modifiers may provide therapeutic routes to promote CAG contraction or prevent further expansion, while modifiers of mRNA disruption may provide targets to prevent the death of neurons.

If I were to take you into my lab right now to show you the most exciting thing happening there, it wouldn’t be an experiment, it wouldn’t be a particular project - it would be the people.

Christopher E. Pearson, PhD The Hospital for Sick Children (SickKids) University of Toronto

JENNy MoRToN, PHD, SCD, FRSB

Institution: University of Cambridge, England

Project Title: Can core body temperature be used as a readout for changes in metabolism in Huntington’s disease?

It has long been suspected that changes in metabolism are important in Huntington’s disease because so many patients become very thin. But metabolism is complex and difficult to study in humans, so evidence for metabolic defects in people with HD is scarce. We know from a metabolomics study that dozens of metabolites are abnormal in presymptomatic HD sheep. In this project, Dr. Morton will use thermal imaging of sheep to see if core body temperature that is directly related to metabolism is different in HD sheep compared to normal sheep. She will then determine if temperature regulation deteriorates further in the HD sheep as the disease progresses. If this is the case, then core body temperature could be used as a non-invasive ‘surrogate’ biomarker to track metabolic changes in HD.

CHRiSToPHER NG, PHD

Mentor: David Housman, PhD

Institution: Massachusetts Institute of Technology, Cambridge

Project Title: Characterization of genetic variants that modify age of onset in Huntington’s disease

Dr. David Housman helped pioneer the 1983 discovery of the genetic marker for Huntington’s disease. The Housman lab now studies how the rest of the human genome controls the age at which a person with the Huntingtin mutation becomes symptomatic for the disease.

A postdoctoral fellow in the Housman lab, Dr. Ng plans to identify other genetic markers that modify HD age of onset. To do so he is using the extensive collection of patient samples and clinical data collected in Venezuela over a 23-year period from the world’s largest HD family. He will characterize the malfunctioning of proteins encoded by the genetic variants in HD patient samples and in mice models. Further, he aims to discover the role of modifier variants in the pathology of the disease by genetic manipulation in cells from people with HD and in HD mice models. Understanding how these variants alter the course of the disease will help distinguish the molecular pathways that are most capable of modulating Huntington’s age of onset. By going from genetic to molecular insights, he hopes to target these modifier pathways to develop protective therapies capable of slowing HD pathology.