Summaries of 2016 HDSA-Funded HD Human Biology Projects

madeleine-sharp Striatal-dependent reward processing: A substrate for early behavioral symptoms in Huntington’s disease

Madeleine Sharp, Assistant Professor, McGill University, Canada

Huntington’s disease affects a part of the brain called the striatum that we know is very important for controlling behavior. The striatum sends signals about the ‘rewards’ experienced in our environments to the rest of the brain. These rewards can be anything: a delicious meal, attaining a goal, a nice hug, or a good grade. The ability to properly send signals about these rewards is critical because most of what we think, remember, learn and do is controlled or guided by reward: we remember positive experiences, we learn from good outcomes, we strive to do well and we pay attention to what matters.  In the early stages of HD, most of the disease in the brain is in the striatum. If the striatum is so important for informing the rest of the brain about reward, could reward signaling be impaired in patients with HD? Also, we know that the majority of people with HD experience behavioral symptoms like loss of motivation or a tendency to perseverate on certain ideas or actions. Since these symptoms happen even in the early stages of the disease, can these symptoms be explained by an inability of the striatum to properly signal rewards? In fact, we know that in people with other diseases that involve the striatum such as Parkinson’s disease, these symptoms are related to abnormal reward signals in the striatum. But this has never been tested in HD.  The goal of this project is to determine if reward signaling is impaired in people with HD. We think that this could help us design better treatments for behavioral symptoms.



wasim-malikOculomotor assessment as a potential biomarker for Huntington’s disease

Wasim Malik, Assistant Professor, Harvard Medical School/Massachusetts General Hospital

The goal of our research is to develop a novel eye-movement technique to aid the diagnosis and progression monitoring of Huntington’s disease (HD). We will conduct a pilot study using a portable eye-tracking system, with custom-developed analysis software. We will identify abnormal eye-movements that may indicate the presence and severity of HD. We will then use state-of-the-art techniques in machine learning and big data analytics. These analyses are inspired from great successes in real-world medical problem-solving also used by Google, IBM Watson and others. By analyzing the unique data through innovative artificial intelligence approaches, we expect that work will lead to a better way for HD’s early diagnosis and to monitor its progression. Ultimately, this technique may be used to improve clinical trials and clinical management in HD.



steven-marineroBrain infiltration of peripheral blood mononuclear cells in driving neurodegeneration in Huntington’s disease

Steven Marinero, Graduate Student, Duke University

While much study has been devoted to genetic “triggers” of CNS neurodegeneration—notably mutant Htt in Huntington’s disease (HD)—such inherited triggers are typically expressed from early fetal development and are fundamentally inaccessible to timely clinical intervention. In contrast, later and significant “drivers” of the forward rate and extent of disease pathogenesis may present as more favorable and effective therapeutic targets. In this context, the present proposal focuses on neuroinflammation as a likely significant driver of later stages of HD disease progression. Peripheral macrophages are especially favorable targets because of their location in an easily drug accessible compartment, namely the blood, prior to their infiltration into the brain in later stages of disease. Yet defining relative roles for infiltrating peripheral blood monocyte-derived macrophages (MDMs) vs. endogenous microglia in CNS disease has been challenging. Here, we will take an ex vivo engraftment strategy which will give us a unique opportunity to investigate the role of MDMs in a bona fide brain tissue setting where the identities of infiltrating MDMs vs. endogenous brain microglia can be clearly distinguished. In particular, we will be able to ask the critical question of whether MDMs from HD patients have altered functional impact on HD neurodegeneration, enabled by support and collaboration from the HDSA Center of Excellence at Duke.



natalia-pessoa-rochaMicroglial activation in HD: A structural and functional study

Natalia Pessoa Rocha, Research Fellow, University of Texas Health Science Center at Houston

The objective of this study is to investigate (try to figure out) the role played by microglia in different stages of Huntington’s disease (HD). Microglia are the brain immune cells. They play an important role as mediators of inflammatory response to infection and injury inside the brain. For this, we intend to do a positron emission tomography (PET) scan and blood analyses. A PET scan is a type of imaging test. It uses a radioactive substance called a tracer to look for some characteristic in the body. In this study, we will use a radioactive substance to trace microglia in the brain. In addition, we will collect peripheral blood in order to analyze the profile of blood immune cells. Then, we will try to analyze whether inflammation in the brain (through PET scans) is associated with inflammation in the blood (through blood exams). This will help the study doctors (researchers) to understand the immune / inflammatory mechanisms that are involved in HD. The results obtained from patients with HD in different stages will be compared with controls (i.e., individuals with no neurological disorder). The researchers expect to increase the understanding of physiological changes associated with HD (mainly immune system-related changes). Our results can foster the development of new therapeutic interventions targeting inflammation in HD.




alan-phippsEfficacy of tDCS for improving gait in HD

Alan Phipps, Graduate Student, Indiana University

Impaired gait has a tremendous impact on the lives of Huntington’s disease (HD) patients, limiting their ability to safely navigate their surroundings. This deficit puts HD patients at an increased risk of falling. Such difficulties in gait may result from the over-excitability of the brain’s motor cortex that occurs after degeneration of certain basal ganglia pathways in HD. Here we propose to investigate the potential of transcranial direct current stimulation (tDCS) to improve gait and brain excitability in HD patients. tDCS is a safe, noninvasive brain stimulation technique that can painlessly increase or decrease the excitability in a targeted region of the brain. Current research shows that tDCS is effective in improving motor function and brain excitability in stroke and Parkinson’s disease patients. This would be the first study to investigate the potential benefits of tDCS in HD patients. To assess gait, subjects will walk on a motorized treadmill for 10 minutes.

While walking, footswitches placed in the subject’s shoes will allow us to determine foot placement timing during gait. Additionally, electrical activity from several lower limb muscles will be recorded during gait by taping electrodes to the skin. We predict that inhibitory tDCS in HD patients will decrease brain excitability and improve gait. If so, this would suggest that tDCS could be used to counteract over-excitability of the motor cortex in HD patients, yielding improved gait. With no cure for HD available, treatment goals are to limit symptom management, frequently by pharmacological means. Unlike medications used to manage HD, tDCS has no side effects. This study may have important implications for daily functioning and fall risk in HD patients by reducing brain excitability and therefore improving gait.



rocio-gomez-pastorPrevention of abnormal degradation of the neuronal protective factor HSF1 in Huntington’s disease.

Rocio Gomez-Pastor, Research Fellow, Duke University

HD is caused by a variation in the HTT gene that encodes a protein (huntingtin) that misfolds, thereby causing dysfunction and death of neurons and muscle cells. Under normal conditions cells possess molecular machinery, orchestrated by the master regulatory protein HSF1 that prevents protein misfolding and maintains cell function and viability. However, in cellular and mouse models of HD, and most importantly, in HD patients, this machinery is impaired. We have identified why the HSF1-dependent cellular protection mechanism is defective in HD, not only in the brain, but also in small biopsies taken from the leg muscle. We have demonstrated that inhibition of the HSF1 degradation process has potential for HD therapy in mice and that the inappropriate HSF1 degradation machinery is conserved from mouse HD models to a limited number of human HD patient samples. This project proposes to determine if the HSF1 degradation machinery is found in tissues from both postmortem HD patient brain, and in living HD patient muscle, skin and fat to validate the involvement of this pathway in Human HD patients. Since we have demonstrated that modification of the HSF1 degradation pathway improves symptoms in a mouse HD model, demonstrating the conservation of this pathway in humans will provide a strong foundation for developing therapies through the HSF1 protective mechanism in humans.


lisa-salazarMolecular and cellular assessment of huntingtin lowering in differentiated patient-derived HD iPSCs.

Lisa Salazar, Assistant Project Scientist, University of California at Irvine

Huntington’s disease (HD) is a devastating neurodegenerative disease that strikes in the prime of life. Patients experience progressive impairment of motor and cognitive function, as well as other symptoms, and treatments to slow disease progression remain elusive. Because disease is caused by mutation of the huntingtin (HTT) gene, one strategy for disease intervention, now in clinical trials, is to reduce production of the HTT protein. Using HD patient-derived stem cells, we are generating cell lines in which total or mutant HTT levels can be reduced at the stem cell stage, or any time during their development into mature neurons. This will allow us to evaluate the consequences of reducing total HTT compared to those of preferentially lowering mutant HTT.  This is important because the question remains whether decreasing expression of wild-type HTT will have more subtle adverse effects. This strategy will further enable us to begin to identify which disease characteristics can be rescued, especially when intervention is given to more mature cells, as it would be in patients. Specifically for the proposed studies, we will examine the ability of HTT lowering to rescue gene expression, cell viability and metabolic function, resulting in the identification of relationships between gene expression and cell function that might inform benefits and side effects of HTT lowering treatments and provide signatures amenable to rescue that can be targeted in small molecule screens.



mosierphoto-2Proximal Huntingtin Protein Interaction Networks in Human Juvenile and Early Adult HD Brains Analyzed by Proteomics and Systems Biology

Charles Mosier, Research Associate, University of California at San Diego

Huntington’s disease (HD) is caused by trinucleotide repeat (CAG) expansions in the HTT gene, encoding huntingtin (Htt) protein with increased polyglutamine (polyQ) tract. Juvenile HD patients with >60 repeats display early age of onset in children compared to adult HD patients with ~38-55 repeats, while normal patients have 10-35 repeats. The tremendous difference in age of onset of juvenile and adult HD predicts differences and similarities in mutant Htt protein interactions that lead to neurodegeneration and deficits. Therefore, the goal of this human-focused project is to investigate human juvenile HD brains for Htt interacting proteins that will be evaluated for mediating mutant Htt-induced neuronal cell death. Data will be compared to parallel studies on human adult HD brain tissues (including early stages of the HD disease process) for Htt protein interactions. This research will assess the hypothesis that juvenile HD involves distinct and similar sets of proteins interacting with mutant Htt in a polyQ-length dependent manner to initiate molecular pathways leading to neuronal cell death, compared to human early adult HD. Results will define differences and/or similarities in mechanisms for early onset juvenile HD compared to adult HD. Findings will logically lead to new drug target opportunities to address the unmet need for effective therapeutic drugs to improve the lives of juvenile and adult HD patients.


veronica-hdsa-headshotStudy of mitochondrial outcomes as biomarkers of Huntington´s Disease progression and/or readouts of pharmacological interventions

Veronica Ines Brito, Research Fellow, University of Barcelona Medical School

In people carrying the HD genetic abnormality, many brain cells become damaged and eventually die even before the main outward symptoms appear. Thus, timing of the brain changes and the outward symptoms of HD are completely disconnected. Therefore, HD treatment success requires intervention at early disease stages before extensive brain cell loss. To achieve proper neuroprotective therapies we need tracking tools known as biomarkers to monitor the status of the disease and the early brain changes. Among different pathological processes there is much evidence implicating mitochondria alterations in cell problems since mitochondria produce the vast majority of energy but also damage and highly reactive molecules. Moreover from research in HD and other human diseases there is growing evidence that the same mechanisms of disease can be shared by the brain and peripheral tissues. Importantly, in HD the mutant protein is expressed in almost all cells. With this in mind, we would like to explore and identify in dermal fibroblast obtained from control and HD patients´ biopsies (pre-symptomatic and symptomatic) different signs of mitochondrial dysfunction. We will focus in mitochondrial processes previously described to be altered in HD brain such as mitochondrial dynamics, bioenergetic and oxidative stress and we will correlate these outcomes with different clinical characteristics. Moreover we will explore for alterations in the expression of newly DNA-like molecules (miRNAs) that can affect mitochondrial function in these peripheral tissues. This part of the study has the potential to find novel aberrant miRNAs associated to mitochondrial dysfunction but also to identify other miRNAs in dermal fibroblast that could reveal specific targets for treatment or biomarkers of disease progression.

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