Instructor at Massachusetts General Hospital
Mentor: Jacob Hooker, PhD
Project Title: COX-2 PET radiotracers for imaging early HD pathology in the living brain
To develop effective therapeutics for Huntington’s Disease (HD), we need to understand biological changes in the living brain that occur at the earliest evidence of disease conversion. Imaging with positron emission tomography (PET) allows researchers and clinicians to measure how critical targets, such as proteins or enzymes, change in the living brain, at disease onset and throughout disease progression. More importantly, PET can measure how a target changes following therapeutic intervention, a critical step in assessing treatment efficacy. The study of these critical targets with PET requires specific molecules tagged with a radiolabel (radioligands). Although many radioligands have been developed over the years for PET and neurodegenerative disease, no PET ligands have been able to predict disease conversion or aid prognosis in HD. Therefore, it is imperative that we develop new PET radioligands that allow us to monitor important molecular changes in the living brain of HD patients. Our studies show that a particular protein, cyclooxygenase-2 (COX-2), is dramatically altered in the HD brain, even in premanifest HD. Our data indicates COX-2 holds promise as a novel clinical marker of HD onset and progression. We will develop COX-2 selective PET radiotracers that will enable the study of disease mechanisms in the living HD brain. We believe this research will provide an objective clinical marker that can assess, and lead to the discovery of, effective disease-modifying therapeutics for HD patients.
Instructor at University of Massachusetts Medical School Mentor: Neil Aronin, PhD
Project Title: Alternative polyadenylation of the human HTT mRNA and its effect on mutant HTT accumulation
The central dogma of molecular biology describes the conversion of genetic information in DNA to an RNA template (messenger RNA or mRNA), which directs the production of a protein. In Huntington’s disease, a mutation in the DNA leads to production of a toxic protein. The mutant huntingtin (HTT) protein has been widely studied, but we know less about the mRNA. The Huntingtin gene produces several distinct mRNAs. Three of these mRNAs can produce identical full-length HTT protein. However, these different mRNA don’t have the same stability and can be found at different locations within the cell. These changes can have profound impacts on the function of both the mRNA and the protein, and may lead to differences in protein abundance. In the brain of Huntington’s disease patients, there are changes in the relative amounts of the various HTT mRNAs. Recent work has indicated that the location of the HTT mRNA changes in cells expressing mutant HTT. We will study human fibroblasts to understand whether these changes affect Huntington’s disease pathology. Do different HTT mRNAs produce more protein? Do changes in the HTT mRNA change its location within the cell? If certain forms of the HTT mRNA produce more protein, targeting specific forms of the HTT mRNA could be therapeutic. Understanding the processing of the HTT mRNA could lead to RNA modifying therapeutic targets for HD.
Neuropathology Fellow at Columbia University
Mentors: Ai Yamamoto, PhD, and Jean-Paul Vonsattel, MD
Project Title: Aberrations in autophagy in the human brain of Huntington’s disease: a post-mortem study with correlation to murine models
Searches for a cure for HD have largely focused on understanding why the nerve cells die and testing experimental treatments using genetically engineered mice that are designed to have a similar biology to human HD. In human HD, a protein called Huntingtin, is abnormally produced, moves to the nucleus of the cell and aggregates. Autophagy refers to the breakdown of proteins within cells, and abnormalities in this process has been implicated in mouse models of HD, which may partly explain the accumulation of Huntingtin protein. However, little work has been performed in the human condition and uncertainty persists as to how well these mouse models replicate the human disease. This is most likely because of the lack of well-characterized, human HD brains available for basic research. This study sets out to increase the number of HD brains available for research and is carefully designed to investigate autophagy defects in specific brain regions of HD. Understanding precisely what aspects of autophagy may be impaired in the human disease may provide drug targets to slow or halt the disease process.
Postdoctoral Fellow at Université Laval
Mentor: Sébastien Hébert, PhD
Project Title: Importance of microRNA biogenesis deficits in Huntington’s disease
Like DNA, RNA carries genetic information necessary for life. A class of small RNA molecules, termed microRNAs, is essential for brain development and the survival of neurons. Recently, we and others have identified a number of microRNAs that are modified in neurodegenerative diseases. Interestingly, individuals with Huntington’s disease seem to have a unique (abnormal) profile of microRNAs in the brain. Some changes occur early in the disease process suggesting that microRNAs function before or in parallel with the mutant huntingtin protein to promote neuron loss and clinical symptoms. This observation is important, since we still don’t know how mutant huntingtin impairs the brain. In this study, we aim to understand why microRNAs go awry in HD, with the ultimate goal of restoring their normal function. Our proposed experiments will also be important for current preclinical and clinical trials aimed at lowering mutant huntingtin in patients. Indeed, most of these therapeutic strategies depend on intact microRNA function in the brain. Therefore, the implications of our findings are twofold: to better understand the molecular causes of Huntington’s disease, and to complement current therapies.
Postdoctoral Fellow at University of Copenhagen, Center for Translational Neuromedicine
Mentor: Steven A. Goldman, MD, PhD
Project Title: Epigenetic dysregulation of oligodendrocyte differentiation and myelinogenesis in Huntington’s disease, and its relationship to disease-associated neuropsychiatric pathology
Research on HD has long been focused on loss of striatal medium spiny neurons. More recently though, a contribution of glial cells (support cells in the brain) and white matter pathology to HD has been described in animal models and humans. Glial cells include mature oligodendrocytes, which produce myelin to act as insulators for electrical messages along neuronal axons. When oligodendrocytes are damaged, myelination is deficient, messages are disrupted, and thinking and behavior are affected. In Huntington’s disease, myelin damage and white matter loss correlates with the appearance of behavioral and psychiatric symptoms that often precede motor deficits. Psychiatric symptoms are associated with a significant white matter loss and abnormal gene expression by glial cells like oligodendrocytes. There is emerging evidence that epigenetic regulation (modifications to DNA) plays an important role in oligodendrocyte development by controlling both their gene expression and ability to myelinate axons. We will use induced stem cells donated by HD patients, and differentiate these as oligodendrocytes to model how mutant huntingtin affects them and their gene expression. We expect to provide the basis for a new therapeutic approach, of targeting epigenetic modifications and their effectors to restore normal glial maturation and insulation of communicating neurons.