Alby Richard, MD, PhD
Mentor: Samuel Frank, MD
Oculomotor Learning as a Biomarker in Huntington’s Disease (HD) patients
Despite the well-established genetic cause of Huntington’s Disease (HD), the mechanisms contributing to the progressive motor dysfunction in HD are not fully understood. In the current era of novel treatments for HD, there is a great need for a rapid and relatively non-invasive approach to track disease progression and response to treatment. The differences in motor control between pre-symptomatic individuals and non-HD controls are often subtle, and motor learning tasks offer a promising way to identify these early.
Learning a new motor action or skill requires that the musculoskeletal system gain and perfect novel movements with repeated practice (e.g., learning to play tennis). Any such action requires the coordinated activity of a number of muscles and joints, along with sensory feedback to produce the finely tuned movements leading to the desired behaviour. Previous studies of motor learning using reaching movements have revealed that HD patients are more jittery than age-matched controls, and that it takes longer to learn and consolidate a new movement sequence.
Arm movements are difficult to study as a sensitive marker of disease onset and progression however, since many factors can impact task performance and bias the results (e.g., involuntary movements, which are common in HD). By contrast, eye movements are among the best studied and understood examples of motor control in biology, and can be measured with ease and accuracy using non-invasive eye-tracking techniques. Moreover, eye movement experiments in HD have the benefit (compared to limb movement paradigms) of being less susceptible to artefact and noise from involuntary movements.
Charlene Smith-Geater, PhD
Mentor: Leslie Thompson, PhD
Modulation of E3 SUMO-ligase PIAS1 in 3D cortico-striatal assembloids and investigation of theHD relevant CSF SUMO-ome
Recent news of HTT lowering trials pausing has reinforced the need to pursue alternative or complementary therapeutic avenues. In the Thompson lab, we have been working on an alternative therapeutic approach, reducing the amount of a protein, PIAS1, in the brain. Two different HD mouse models and stem cells derived from HD patient skin cells were evaluated for the effect of altered PIAS1. PIAS1 plays a role in attaching proteins, called SUMO, to other proteins which changes how they behave and how well they carry out their cellular tasks. Our data shows thi sprocess is disrupted in HD. Our work has shown there is potential benefit for reducing PIAS1 in the striatum (in mice)and in human cells and we seek to explore this further in an even more relevant human model. I will work with HD patient stem cells, in which we have reduced the amount of PIAS1, and make them into 3D structures called organoids that resemble areas of the brain, the striatum and cortex (both affected in HD). I will then investigate cellular processes that we know are disrupted in HD, including somatic repeat instability, and see if reducing the amount of PIAS1 is beneficial. These studies include investigating the function and structure of the powerhouses that generate energy for the cells (mitochondria), how the cells communicate with each other (synapses), how well the cell repairs its DNA and whether the cells are expressing the correct genes. Additionally, I will examine HD patient cerebrospinal fluid (CSF) to determine levels of SUMO protein and what proteins it has been attached to or is interacting with. These CSF studies are aimed to help us understand more about what goes wrong in HD and may provide clues to a new therapeutic readout when testing how well drugs work for patients.
Joan O’Keefe, PhD, PT
Mentor: Deborah Hall, MD, PhD
Neural underpinnings of cognitive, balance and gait deficits in Huntington’s disease
Huntington’s disease (HD) is a neurodegenerative disease characterized by complex cognitive, gait, and balance deficits which cause reductions in activities of daily living (ADL), increased risk for falls, significant disability and poor quality of life. Patients with HD have difficulty multitasking and their cognitive deficits exacerbate gait and balance deficits, contributing to falls and greater disability. In order to develop preventative and rehabilitative therapies for cognitive and motor deficits in HD it is important to understand the brain activation patterns underlying these cognitive-motor relationships. This research project will examine the extent that different cortical brain regions are activated in individuals with HD during cognitive, balance and walking, and multi-tasking conditions by using a novel, noninvasive, and wireless functional near infrared spectroscopy (fNIRS) technology. fNIRS is a reliable neuroimaging technique that measures blood flow alterations in the brain and can be worn with little to no restrictions on one’s mobility. We will combine this with the use of portable inertial sensors to measure gait and balance deficits during challenging and ecologically valid gait and balance tasks. We will also perform imaging of the brain via MRI to obtain volumetric measurements of different cortical regions to explore the structure-function relationships mediating cognitive, balance and gait dysfunction in HD. Completion of this research study will identify the expected abnormal cortical activation patterns and structural changes in several cortical brain regions during complex cognitive, balance, and gait tasks in HD. This highly innovative research will lay the foundation for the field of dynamic functional imaging and establishment of neural structure-function relationships in HD. This research will also inform future rehabilitation and therapeutic studies and provide outcome measures to monitor their efficacy in future clinical trials, which is needed to improve health care and quality of life for HD patients and their families.
Ana Gámez-Valero, PhD
Mentor: Eulàlia Martí, PhD
Plasma extracellular small RNAs as early biomarkers of Huntington’s disease and indicators ofdynamic changes in disease progression
In Huntington’s disease (HD) the expanded CAG repeat in the Huntingtin (HTT ) gene is pathogenic through mechanisms involving both, the mutant protein, and the CAG repeat RNA derived from the transcribed gene. In addition, small RNAs (sRNAs) produced in HD have recently been uncovered as toxic drivers. Many of these species, including micro RNAs and tRNA- derived fragments, are bioactive compounds essential for the normal brain function which are strongly and early perturbed in HD.
In different neurodegenerative diseases, including HD, the deregulation of sRNAs expression have been shown to occur early before clinical symptoms start. These changes can be peripherally detected in plasma, where sRNAs circulate either free, bound to proteins/lipids, and/or encapsulated within extracellular vesicles (EVs). EVs are released by all cells and its content, including sRNAs, may reflect the physiological and pathological state of the cells of origin. Therefore, the analysis of EVs- sRNA content offers an exciting source of biomarkers to detect the earliest alterations. Moreover, different studies have reported that the vast majority of sRNAs are found outside EVs in the extravesicular milieu, but their biomarker potential has been little explored.
We propose that circulating sRNAs in vesicular and extravesicular plasma compartments offer complementary layers of information that will help in defining premanifest and prodromal changes in HD. Here, we will deeply characterize sRNAs found in EVs and extravesicular plasma sub- fractions, both at premanifest and manifest stages, compared to healthy individuals, and in a longitudinal follow- up, using exhaustively characterized cohorts. This study should contribute to overcome the challenge for physician and drug developers to predict the course of HD. Our results will be important for a better patients’ management and clinical care, and may facilitate patients’ stratification during preclinical trials, being an important step for the future advancement of therapeutic development and for identifying optimal treatment windows.
Tamara Maiuri, PhD
Mentor: Ray Truant, PhD
Poly ADP-ribose dysregulation in HD patient samples and potential for therapeutic intervention
Thanks to the participation of thousands of HD patients in clinical studies, we now know that it may be possible to delay disease onset by targeting DNA repair pathways. Our research group has found that the huntingtin protein is involved in a step of the DNA repair process called poly ADP-ribosylation. Drugs targeting this step have been developed for cancer treatment, but we do not yet know whether it makes sense to repurpose these drugs for HD.This project will carry out preclinical analysis to explore this potential therapeutic avenue.