2017 RESEARCH

Your Dollars At Work:

A Look at NAF Funded Research

NAF is pleased to announce that we provided funding for 27 promising Ataxia research studies for fiscal year 2017. Research studies will take place in United States, Canada, Australia, Germany, the Netherlands, and Portugal. A summary of the completed research studies will be published in Generations in 2018.

SEED MONEY GRANTS

Ana Teresa Antunes Simões, PharmD, PhD
University of Coimbra
Portugal

Calpain-mediated proteolysis in Machado-Joseph disease Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most frequent worldwide autosomal dominantly-inherited ataxia, which means that affected individuals have a 50% chance of transmitting the affected gene to their children. In MJD, a mutation leads to a bigger-than-normal stretch of polyglutamine at the ataxin-3 protein. The ataxin-3 protein is a biological molecule that is important for cellular quality control. Researchers believe that ataxin-3 is cut into smaller fragments. Our research team and others have recently shown that the molecules responsible for the breakdown of ataxin-3 are called calpains. Calpains form toxic fragments, move the ataxin-3 from the cytoplasm to the nucleus, and contribute to degeneration of neurons. The aim of this project is to understand, at a cellular level, calpains’ contribution to the development of MJD. To achieve this aim, we will evaluate how genes encode the calpain system, determine in which places ataxin-3 is cut, and how calpains are activated according to the different brain regions, cell types and timeline for disease progression. Moreover, because no current treatment is available, we will evaluate whether a novel calpain inhibitor can reduce cell injury and alleviate loss of motor coordination. These expected results could be used to develop a therapy for MJD patients in a short-time frame. The results can also be used to identify biological measures, or markers, of MJD progression or treatment response. Furthermore, understanding the calpains’ role in MJD can inform our understanding of other ataxias that are vulnerable to calcium deregulation.

Sandra de Macedo Ribeiro, PhD
Instituto de Biologia Molecular e Celular
Porto, Portugal

New therapeutic approaches for Machado-Joseph Disease: Chaperoning protein self-assembly Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease, is a rare neurodegenerative disease. No therapy is currently available for SCA3. SCA3 is caused by an expanded stretch of CAG triplets in the affected gene. The overrepetition of CAG causes a protein called ataxin-3 to form abnormally—and in a way that is toxic to neurons. For the past 20 years, researchers have made impressive progress in understanding the cellular functions and formation of ataxin-3, but so far no specific treatments are available for SCA3. We need to better understand the three-dimensional structure of ataxin-3 to fully determine its function and dysfunction at the molecular level. By understanding more clearly how ataxin-3 becomes toxic, we can also learn how to develop targeted therapies. We propose to study a number of synthetic molecules that can bind and reshape ataxin-3 into a non-toxic form. If we can determine how ataxin-3 is shaped with atomic precision, we can hopefully identify which molecules can serve as the best therapy to treat the dysfunction.

Gulin Oz, PhD
University of Minnesota
Minneapolis, MN

Launching the US-Europe Neuroimaging Partnership in SCA A major challenge in developing therapies for spinocerebellar ataxias (SCAs) has been the lack of highly accurate imaging markers for (1) detecting changes due to SCA in the cerebrum and cerebellum and, consequently (2) evaluating the effectiveness of treatments being studied. Although researchers have developed clinical scales that can be used to assess response to treatment, they have several limitations. One important limitation is that results can be highly variable. Therefore additional non-invasive imaging tests are still needed to measure the direct effects that potential treatments have on the brain. In this project, we will bring together two ongoing efforts in the United States and Europe to validate imaging markers for SCA3. SCA3 is the most common SCA in the world and affects about 30% of all families with a history of dominant ataxia. Currently, there is no causal treatment for SCA3. However, as we continue to understand the way that SCA3 progresses at the cellular level in the body, several new treatment approaches are being or will be tested in clinical trials. To ensure strong outcomes from these trials, we wish to take advantage of an ongoing, NIH-supported imaging study that focuses on chemical markers of SCA3. We intend to add a magnetic resonance (MR) imaging component to that study so we can get detailed structural and functional MR data, which will also be part of an ongoing European study called the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI). Funds from the NAF Research Grant will allow us to initiate a US-Europe imaging collaboration that is long overdue. This collaboration can help validate noninvasive MR biomarkers for upcoming SCA3 trials taking place in many sites throughout the world.

Susan Perlman, MD
UCLA
Los Angeles, CA

Web-based National Ataxia Database The National Ataxia Registry, the National Ataxia Database, and the Ataxia Tissue Donation Program were formed to provide the infrastructure for clinical research in the ataxic disorders. They enabled ataxia researchers to notify ataxia patients of upcoming research projects, to store and analyze data from those projects, and to examine tissues from ataxia patients to find out how ataxia develops and how the body responds to it. The web-based National Ataxia Database is currently housed on the UCLA computer servers, and over the years since its development, has provided natural history database support to the UCLA Ataxia Clinic, as well as to the Ataxia Clinic at John Hopkins University. Other "Ataxiologists" in California, Arizona, Nevada, and Colorado have expressed interest in using it as well. It has begun to provide a platform to support and join specialists in clinical care and clinical research of ataxia. It will ultimately assist all members of the Ataxia Clinical Research Consortium in future collaborative endeavors in clinical research and in setting standards for clinical care. Following the end of funding from the National Institutes of Health for the Rare Disease Network, with of the help of the NAF "bridge" grant, we were able to continue to import the existing data of the natural history study into the National Ataxia Database. This allowed us to continue enrollment and follow-up of participants in this important study of SCA l , 2, 3, and 6. Data collection will begin on participants with SCA 7, 8, and 10. There are now 13 sites contributing to this project, and six more will be added. Close to 500 participants have been enrolled and are pursuing natural history examinations and banking of specimens. The National Ataxia Database will also be open for ataxia researchers to "bank" other clinical data collected, either in the individual's private data docks (not accessible to other ataxia researchers) or in data docks shared by several researchers. (e.g., for a proposed project to look at coded clinical data on people with sporadic ataxia). Templates will be added for scales to measure fatigue, dizziness, cognition, and neuropsychiatric symptoms. The National Ataxia Database is an essential tool for the Clinical Research Consortium for the Study of Cerebellar Ataxia.

Martin Lavin, PhD
University of Queensland Centre for Clinical Research (UQCCR) Australia

Assessing the role of senataxin in cellular inflammation, gene regulation, and innate immunity in Setx-/- mice and a human neuronal model. Ataxia oculomotor apraxia type 2 (AOA2), a progressive form of cerebellar ataxia, is a neglected rare neurological disorder that develops mostly in late adolescence to early teens. AOA2 occurs from mutations in the SETX gene. The SETX gene encodes the senataxin protein, which plays a key role in the response to DNA damage and regulation of gene expression. Although researchers have described many mutations in the SETX gene, we know very little about the mechanism of disease progression, and no specific treatment exists for AOA2. Currently, the primary way to manage the disease is to provide supportive care (care that does not treat the disease but instead keeps the patient comfortable). In 2015, while collaborating with Dr Ivan Marazzi at Columbia University, our research team described an unanticipated role that senataxin plays in controlling innate (natural) immunity, the part of the immune system that responds immediately when a toxin or other foreign substance appears in the body. The involvement of senataxin in innate immunity offers new insight into a possible link between neurodegenerative disorders and inflammation. This finding provides a new framework to explore more fully the possibility that infection and a de-regulated innate immunity may contribute to the development of AOA2—and potentially other neurodegenerative disorders. The purpose of this research project is to assess the role of senataxin in cellular inflammation, gene regulation and innate immunity. Our aim is to gather more knowledge of the how AOA2 begins and then progresses. Specifically, we want to better understand the molecular changes that are involved in AOA2—by (1) further narrowing down the role of senataxin in innate immunity and (2) identifying critical genetic and cellular pathways that are involved in the development of the disease. Advancing an understanding of the cellular function of senataxin and its role in the disease process for AOA2 will be key as researchers help develop effective therapy for patients who have AOA2.

Clara Van Karnebeek, MD, PhD
University of British Columbia
Vancouver, BC, Canada

Whole Exome Sequencing in the Diagnosis and Management of Atypical Childhood Hereditary Ataxia Conditions. The National Ataxia Foundation (NAF) was formed by John and Henry Schut in 1957 to promote awareness of the degenerative ataxias, support research into the causes and cure of the disease, and provide support and comfort to ataxia patients and their families. We are resolved to advance these primary objectives through our project “WES in Atypical Childhood Ataxia.” New technologies have drastically changed the way we diagnose rare diseases. The human genome contains about 3 billion bases or letters. For over a decade, researchers have had the ability to read a person’s entire genome through a process called whole genome sequencing (WGS). However, we were not able to translate the DNA code into information that we could meaningfully use (for example, for treatment or predicting risk of disease). Now, through testing known as whole exome sequencing (WES), we can now focus in on the “coding” portion of the genome, called the exons, that provides instructions for making proteins. WES methods allow the body’s entire set of instructions—or exome—to be examined as a single laboratory test—rather than having to individually analyze all 20,000 genes that make up our exome. Through WES, we are able to look for “spelling mistakes” (known as pathogenic mutations) in gene(s) and then determine if these changes are the cause for the person’s illness. With this innovative tool, we aim to enroll and offer WES to 12 children with severe or complex ataxia in order to (1) discover new genes that cause ataxia, (2) expand what we understand about the clinical picture of known human genes that cause ataxia (3) make sense of these rare genetic ataxic conditions at a microscopic “molecular” level so that we can understand, target, treat and potentially cure these disorders. We plan to achieve these goals by merging our center’s unique expertise in combining deep characterization of a patient’s clinical picture (combined physical, neurological and metabolic symptoms) with expertise in WES analysis. Our hope is that this focused study of ataxic cases at our center will positively affect the lives of patients and families, forge the discovery of new genetic ataxia disorders, expand descriptions of known conditions and create new treatment opportunities.

Fang He, PhD
Texas A&M University
Kingsville, TX

Development of a Drosophila model for Spinocerebellar Ataxia type 36 (SCA36) Ataxia of the cerebellum is commonly caused by expanded repeat sequences of DNA—the abnormal over-repetition of DNA sequences. For example, spinocerebellar ataxia type 36 (SCA 36) is a type of cerebellar ataxia caused by a repeat expansion of the six-letter string of nucleotides, GGCCTG. In people without ataxia, only about 3 to 14 repeats of this string of nucleotides appear. But in people with SCA36, the GGCCTG sequence repeats hundreds of times. Although we know that people with SCA36 have expanded repeats of GGCCTG, no one knows exactly how that repetition damages neurons. To better determine how expanded repeat sequences lead to SCA36, my team and I will use genetically modified fruit flies (Drosophila melanogastre) that have expressed up to 100 GGCCTG repeats. Through our research, we will learn more about whether these expanded repeats are themselves toxic to the neurons. By learning how these DNA mutations lead to neuron damage, we hope to shed light on how therapies could target and possibly halt the excessive expression of GGCCTG repeats.

Margit Burmeister, PhD
University of Michigan
Ann Arbor, MI

Autosomal recessive cerebellar ataxias are heterogeneous neurodegenerative diseases, characterized by incoordination of movement and unsteadiness, due to cerebellar dysfunction. Cerebellar ataxia has emerged as the most common clinical presentation of deficiency of Coenzyme Q10 (CoQ10), a vital molecule required for cells to generate energy and to prevent damage from toxic oxygen radicals. The proposed studies will define the causes underlying CoQ10 deficiency in cerebellar ataxia, and its role in neurodegeneration, and may lead to the identification of novel therapeutic targets. The results of our studies may provide important information relevant also to other neurodegenerative diseases.

Adam Vogel, PhD
Centre for Neuroscience of Speech
Parkville, Victoria, Australia

Intensive home based speech rehabilitation for adults with degenerative ataxia Loss of ability to speak is a devastating and inevitable outcome of many neurodegenerative diseases. When people lose their ability to speak, they lose their ability to carry out basic tasks. They can be stigmatized and marginalized, and they often have challenges with employment. In time, they experience a decrease in their quality of life. Hereditary ataxias cause a lack of coordination with gait, speech, and eye and hand movement. No therapies are currently available to stop degenerative ataxia from progressing. However, therapy to improve speech is within reach. My team and I have conducted a successful pilot study that draws on (1) the principles of motor learning and biofeedback and (2) the expertise of a team that specializes in movement therapy and ataxia. We have designed a home-based, intensive 4-week speech exercise program designed to improve speech in patients with hereditary ataxia. The treatment focuses on improving intelligibility and vocal control. We created exercises and feedback to enhance individuals’ ability to monitor their own speech abilities and improvements. The program is suitable for use in a clinical setting, so it can readily be brought into clinical practice. It can also potentially be adapted for a range of other progressive neurological disorders. Funding from the National Ataxia Foundation will be used to develop a controlled, well-designed study that can assess the effectiveness of this program.

YOUNG INVESTIGATOR & Young Investiagor - SCA AWARDS

Bing Yao, PhD
Emory University
Atlanta, GA

Epigenetic Modulation Mediated by RNA-Binding Proteins in Neurodegeneration Ribonucleic acid (RNA) molecules, like DNA, are essential information-carriers in all organisms. RNA is particularly important for making proteins in the body. Proteins that bind to RNA play fundamental roles in controlling different aspects of RNA functions, which are important for neurons to work properly. Dysfunction with RNA-binding proteins often leads to neurodegenerative disorders that cause ataxia. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that usually develops in the late stage of adulthood. It is caused by a 55 to 200 copies of nucleotide “CGG” repeats in the fragile X mental retardation 1 (FMR1) gene. In FXTAS, these extra CGG repeats can restrict the RNA-binding proteins hnRNP A2/B1. This, in turn, leads to the death of critical motor neurons called Purkinje cells, which leads to ataxia. In this NAF Young investigator award application, I hypothesize that RNA-binding protein hnRNP A2/B1 has a novel role to directly bind to DNA and control critical gene expression to influence the life course of Purkinje cells. In the proposed specific aims, I will first study whether and how hnRNP A2/B1 binds to DNA regions of the genome and whether and how restriction of hnRNP A2/B1 leads to Purkinje cell death. I will then use a cutting-edge method called next-generation sequencing to isolate the genuine roles of hnRNP A2/B1 in controlling the expression of genes related to FXTAS. This study will provide novel insights into how RNA-binding proteins help direct the function of normal neuron cells and, conversely, how their restriction can influence the development of ataxia-related disease.

Jill Sergesketter Butler, PhD
University of Alabama at Birmingham
Birmingham, AL

Reduced expression of mitochondrial aldehyde dehydrogenases contributes to metabolic stress in Friedreich’s ataxia Friedreich’s ataxia (FRDA) is a severe form of ataxia caused by decreased production of a protein called frataxin. In patients who have Friedreich’s ataxia, the loss of frataxin protein eventually damages multiple organs, including the heart and pancreas. Cells in the heart and brain are the most sensitive to changes in frataxin levels. Even though frataxin is just a single protein, lower levels of it can cause other cell proteins and genes to stop working properly. The goal of this study is to get new information about how and when frataxin causes those cell and gene changes. As we learn more about those changes, we hope to narrow down which particular signs, or biomarkers, show that Friedreich’s ataxia may progressing in the body. Results from previous research my team and I have conducted show that Friedreich’s ataxia cells have decreased levels of particular enzymes called mitochondrial aldehyde dehydrogenases. The job of these enzymes is to rid cells of certain toxins that can damage heart and brain cells. In this study, we will be further evaluating the levels and activities of mitochondrial aldehyde dehydrogenases in Friedreich’s ataxia cells. In a controlled setting, we will be changing the level and activity of these enzymes to determine how they affect the health and growth of Friedreich’s ataxia cells. In doing this work, we hope to better understand what level of mitochondrial aldehyde dehydrogenase activity is needed to prevent or reverse damage in Friedreich’s ataxia cells. Our findings could help pave the way for new therapies that deliver the right amounts of these protective enzymes into the Friedreich’s ataxia cells—so the ataxia can be treated effectively.

Jana Schmidt, PhD
University of Tuebingen
Germany

Alleviation of proteasomal inhibition as a therapeutic approach for SCA3 Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is caused by the expansion of a repetitive structure within the protein ataxin-3. Proteins that are unwanted or no longer required for brain function are marked in our cells by a certain label called ubiquitin. The cell then degrades the ubiquitin-labelled proteins in a shredder-like process. In SCA3 patients, this degradation process is disturbed, leading to the accumulation of the expanded ataxin-3 and other proteins. Studies of brain tissue have identified collections of protein as a hallmark of the disease in SCA3 patients and also in other neurological disorders. In order to identify the mechanisms leading to SCA3 and to identify ways to prevent the onset of symptoms, we generated mouse models of the disease. Our models allow us to study disease processes in a time-lapse fashion. That means that processes needing decades to take place in man can be studied in a mouse model within months. In our research, we recently studied the process by which ataxin-3 degrades and then applied it to specific mouse models. When we prevented a certain type of ubiquitin label from existing in the mice, we observed that these mice had much less aggregated ataxin-3, did not get the disease and did not develop impaired movement. This means that modulating this ubiquitin label may be a promising therapeutic strategy in SCA3. However, such approaches cannot be directly translated from mouse to man. In our project, we aim to further understand what’s happening inside the cell to lessen the disease in our specific mice. We also hope to figure out whether and how our approach could be translated as a therapy to human SCA3 patients. A successful therapy would help remove the toxic, disease-causing ataxin-3—preventing its aggregation and, consequently, the start of the disease and its symptoms.

Sathiji Nageshwaran, MD
Harvard University
Boston, MA

Transcriptional activation using CRISPR/Cas mutant proteins as a novel therapy for Frataxin gene silencing The underlying cause of Friedreich’s ataxia is the insufficient production of frataxin. The faulty gene that produces insufficient amounts of frataxin contains a GAA mutation. Interestingly, those who have one copy (carriers) of this faulty gene also show up to a 50% reduction in the amount of frataxin protein, but they do not develop any symptoms of Friedreich’s ataxia. Furthermore, the frataxin produced from a faulty copy of the frataxin gene functions as normal. These facts suggest that by increasing levels of frataxin protein to the amount that carriers produce, we may be able to hinder the progression of the disease. This project sets out to increase the production of frataxin by addressing the problem at its source. Because of the presence of the GAA mutation, a cell struggles to access and read the information within the gene. This is because the environment (called the epigenome) in which the gene is now found does not permit the “readers” of the DNA to pass along it. This project will investigate the possibility of improving a cell’s ability to access and read the gene without affecting other genes. The project will make use of the new genome-engineering tool CRISPR, which allows a protein to be targeted to specific genes, but in a manner in which only the environment surrounding the gene is altered and not the gene sequence itself. We hope that changing the silencing environment around the frataxin gene will provide a radical new approach to treating Friedreich’s ataxia.

Vikram Khurana, MD, PhD
Brigham and Women’s Hospital and Harvard Stem Cell Institute Boston, MA

Systematic edgotyping of ataxin proteins in cellular systems from yeast to patient neurons. The identification of gene mutations that cause neurodegeneration offers tremendous hope for understanding and reversing the way neurodegenerative diseases develop. However, researchers have yet to convert genetic insights into real preventive or disease-slowing therapies for patients. Genes code for proteins—the building blocks, signaling molecules and enzymes of our cells. Ultimately, a very significant result of gene mutations is that they lead to abnormal protein changes. We know that gene mutations involved in neurodegenerative diseases lead to some important alterations in protein folding and function, and we know that the mutated proteins collect in affected brain cells. But a global and systematic understanding of these alterations in living cells—and different types of cells—is lacking. To address this lack of base knowledge, we use an unbiased, efficient method, called edgotyping, to systematically look at how gene mutations alter the interactions that take place between affected proteins and the cells they occupy. The edgotyping method can be applied to simple cells (such as yeast) and complex cells (such as brain cells, or neurons—even neurons made directly from patients)—and everything in between. In this proposal, we will be applying edgotyping methods to examine the ataxin protein mutations that lead to spinocerebellar ataxias. We willl systematically define how ataxin mutations (so-called polyglutamine expansions) change the way proteins interact with living cells. The changes in the protein map that result from ataxin mutations have never been examined using edgotyping. But we do know from previous work that some of these changes are important and can be taken advantage of when developing treatments. We have every expectation that the data and platforms we generate in this project will lead to major insights into the biology and treatment of spinocerebellar ataxias, with important implications for neurodegenerative disease in general.

Vincenzo Gennarino, PhD
Baylor College of Medicine
Houston, TX

PUMILIO1 deficiency: understanding a new ataxia gene and its role in cerebellar dysfunction in mice and humans The molecular genetic revolution of the 1990s brought us tremendous knowledge of the genetic mutations that cause many neurological diseases, including many ataxias. Further research into the proteins produced by these genes has revealed that there is another way for a protein to cause havoc in the brain besides being mutated: it might be expressed at levels too low or too high. In the case of several neurodegenerative diseases, including spinocerebellar ataxia type 1 (SCA1) and more common diseases such as Alzheimer’s and Parkinson’s, we have discovered that too much of even the normal version of the disease-driving protein can cause disease. What if we could find a way to lower the levels of these proteins in the brain? Could we slow disease progression? These questions led me to search for the factors that regulate the levels of ataxin1, the protein that is involved in SCA1. I discovered that ataxin1 levels are controlled by an RNA-binding protein called Pumilio1 (PUM1). More importantly, we showed that if you take away PUM1 in a mouse model of SCA1, and ataxin1 returns to normal levels, the SCA1 mice no longer have ataxia. We also noticed, however, that mice lacking Pum1 (the mouse version of the protein is written in lower-case letters) were quite sick: they developed seizures, and they developed ataxia earlier than the SCA1 mice. This led us to suspect that loss of PUM1 function might be the culprit behind some childhood ataxias. In collaboration with medical geneticists around the world, we have identified seven patients with deletion of PUM1 and two patients with mutations in PUM1 who show symptoms similar to the Pum1 mutant mice. This finding confirms our hypothesis that PUM1 deficiency is a genetic cause of an early-onset ataxia syndrome. In this study, we aim to characterize the phenotype of Pum1 mutant mice as precisely as possible and study the effects of loss of function of PUM1 in patient-derived cell lines. This research is necessary to understand how PUM1 deficiency causes childhood ataxias and neurological dysfunction. Our research will also help us understand all the targets of PUM1’s activities in neurons so we can learn whether altering PUM1 levels in the brain could help patients with SCA1 or those with other neurodegenerative diseases.

Marija Cvetanovic, PhD
University of Minnesota
Minneapolis, MN

Role of astrocyte calcium signaling in the pathogenesis of SCA1 Astrocytes are brain cells that neurons need to work normally. Astrocytes help keep neurons alive by giving the neurons nutrients and oxygen and by helping keep the neurons’ environment stable and healthy. The level of calcium within astrocytes affects how well they work. In spinocerebellar ataxia (SCA1), astrocytes undergo a process called astrogliosis, In astrogliosis, astrocytes increase to above-normal levels as a way to protect the nervous system from further damage. In this study, my team and I will be using mouse models to study how astrogliosis affects the level of calcium in the astrocytes. Using astrogliosis as a guide, we will learn whether calcium in astrocytes is changed in the presence of SCA1. We will also test whether changing the levels of calcium in the astrocytes helps prevent or lessen the severity of SCA1 symptoms. If we discover that calcium in astrocytes plays a significant role in the development of SCA1, scientists could one day develop therapies that can change those levels of calcium—and hopefully delay development of the disease.

Manu Ben-Johny, PhD
Johns Hopkins University
Baltimore, MD

Aberrant Regulation of Voltage-gated Na channels in the Pathophysiology of Spinocerebellar Ataxia 27 Spinocerebellar ataxia 27 (SCA27) is a recently identified type of ataxia. Patients with SCA27 experience tremors and difficulties with gait and often perform poorly on cognitive tasks. The genetic basis of this disorder has been localized to mutations within a small protein called Fibroblast growth factor homologous factor 4 (FHF4), which is found within neurons. FHF4 interacts with voltage-gated sodium channels—molecules critical for generation of electrical impulses in neurons. Despite FHF4’s important role in the development of SCA27, the effect of FHF4 on the function sodium channels is not yet fully understood. This prominent gap in the defining the basic mechanisms that govern FHF4 action on sodium channels has clouded our understanding of SCA27, including how this debilitating disorder develops and progresses. Curiously, the sodium channel interface that docks FHF4 also harbors calmodulin, a protein that is found within all eukaryotic organisms, ranging from one-celled organisms to human beings. Calmodulin senses changes in the level of intracellular calcium ions to coordinate the activity of numerous proteins. Thus, it allows cells to attain calcium homeostasis. Our recent work has shown that calmodulin also dynamically reduces the activity of sodium channels in response to increases in cellular calcium levels. This feedback control mechanism allows the cell to reduce generation of electrical impulses in neurons after periods of excess activity. Does FHF4 then regulate sodium channels by overriding calmodulin regulation? Could changes in this interaction then cause changes in electrical properties of neurons as observed with SCA27? To answer these questions, our team will study the interplay between FHF and calmodulin in tuning sodium channel activity within cerebellar Purkinje neurons. We will also explore whether altered dynamics of intracellular calcium ions may play a role in the development of ataxia. Overall, this project promises to advance our fundamental understanding of the molecular interactions that are essential to fine-tune neuronal function and to ultimately evoke coordination of movement. We also hope that these studies will help identify important molecular targets for the development of new therapies for ataxia.

POST-DOC FELLOWSHIP AWARD

Laura C. Bott, PhD
Northwestern University
Evanston, IL

Transcellular regulation of the proteostasis network in Spinocerebellar ataxia type 3 Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an inherited neurodegenerative disorder that is caused by a mutation in ataxin-3. At present, effective treatment is not available for this disease, and researchers do not yet know how neuron dysfunction occurs. Ataxin-3 is present in many tissues, including in cells that are not neurons, and has a role in controlling protein abundance, folding, and transport (called protein homeostasis, or proteostasis). Maintaining protein homeostasis in the body is essential because imbalances in any of these processes can pose a danger to cell function and the health of organisms. We are planning to study protein homeostasis in the tissues of worms that have been genetically engineered to have SCA3. Detailed knowledge of cell type-specific events and regulation across tissues will not only help to improve our understanding of the disease, but also may lead to new treatments for SCA3—and perhaps other neurodegenerative diseases as well.

Stephanie Seminara, MD
Massachusetts General Hospital
Boston, MA

Ataxia with hypogonadotropic hypogonadism due to ubiquitin ligase dysregulation Our research team is investigating a disorder called Gordon Holmes Syndrome. This syndrome adversely affects memory, movement and reproduction. Through our team’s research, we have identified a gene (RNF216), which, when severely mutated, appears to cause Gordon Holmes Syndrome. To further explore the biology of RNF 216, we are studying mice who lack this protein. Our team hopes to use this mouse model to understand how abnormalities in this gene affect neurologic and reproductive health. The long-term goal is to develop better therapies to treat this syndrome more effectively.

James Orengo, MD, PhD
Baylor College of Medicine
Houston, TX

Unraveling the mechanisms of motor neuron degeneration in Spinocerebellar Ataxia, type1 Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive loss of coordination of movements and clumsiness. Individuals affected by this disease typically die between 30 and 70 years of age. Although the majority of scientists study loss of coordination in SCA1, individuals with SCA1 actually die from complications related to weak muscles—not the loss of coordination. In particular, the muscles no longer function well enough for the individuals to breathe properly. My team and I have developed a mouse model for SCA1 that copies the major symptoms of human disease. Based on my clinical background as a neuromuscular disease expert, I made the exciting observation that these mice display signs of muscle weakness as well. In particular, I noted small and sick muscles, breathing abnormalities and muscle stiffness in adult mice. The goals of my project are to examine the molecular changes in these mice that lead to muscle weakness and early death, so that new treatments can be developed.

Ravi Chopra, PhD
University of Michigan
Ann Arbor, Michigan

Identifying Dendro-Protective Ion Channels in Cerebellar Ataxia Purkinje neurons are important brain cells in the cerebellum, the part of the brain that controls balance and coordination. In cerebellar ataxia, Purkinje neurons often break down and eventually die. This process begins with shriveling of the neurons’ dendrites, one of the structures that all neurons use to communicate with each other. Research has shown that the shriveling of Purkinje neuron dendrites play a role in how ataxia symptoms develop. However, researchers do not yet know exactly how and why dendrite shriveling happens. All neurons show electrical activity, which they need to communicate with each other. This electrical activity occurs through the action of a class of proteins called ion channels. In previous studies, my team and I have shown that major changes in Purkinje cell ion channels occur with spinocerebellar ataxia 1 and 2 (SCA 1 and SCA 2). In particular, we have found that the electrical activity in the dendrites of Purkinje neurons changes, and that change could be causing dendrite shriveling. In this new study, we hope to find out which ion channels affect dendrite shriveling. The ultimate goal is to discover news therapies that can halt changes in the ion channels with SCA1 and SCA2—thus reducing ataxia symptoms.

Jonathan Chen, PhD
Scripps Florida
Jupiter, FL

Rapid structure-based lead optimization of a small molecule drug that target r(CAG)exp RNA repeat expansions in spinocerebellar ataxia (SCA) cause degeneration of neurons, which leads to loss of control of body movements. My project will: (1) Characterize the relationship between the chemical structure of a lead (leading) compound and its ability to target overexpression of “CAG” repeats, which are thought to cause several types of SCA (2) Optimize dimeric compounds for bioactivity, selectivity and potency. Dimeric compounds have enhanced affinity for a target RNA over a monomeric compound because binding of one module to the RNA brings a second module within close proximity to the RNA. This increases the chance of the two modules simultaneously binding to the RNA over two separate monomeric compounds. The compounds investigated in this work will reverse the overexpression of “CAG” repeats associated with these SCAs.

Collin J. Anderson, PhD
University of Utah
Salt Lake City, UT

Development and mechanistic study of deep brain stimulation of dentate nucleus for the treatment of degenerative ataxia. Degenerative cerebellar ataxias (DCAs), characterized by incoordination of gait, tremor and motor symptoms, affect 1 in 5,000 people worldwide. Many different causes exist, but each combines the progressive death of Purkinje cells, a common neuron in the cerebellum of the brain. Despite the number of people affected by DCAs and decades of research, treatment options are limited. The loss of Purkinje cells is currently irreversible and leads to changes in the way brain cells communicate, so for any treatment to be successful, it will need to partially reverse these communication changes. Our team believes deep brain stimulation could provide a new form of successful therapy. Using rats that have a loss or Purkinje cells and exhibit tremors and lack of gait coordination, we plan to surgically implant electrodes to repeatedly electrically stimulate targets within the brain and treat DCAs. Deep brain stimulation is frequently used to treat neurological conditions such as Parkinson's disease, essential tremor, and numerous other neurological conditions. The therapy affects the activity of different stimulation targets within the brain in a way that partially restores healthy communication between neurons. The target choice for stimulation in our study will be the dentate nucleus. It is the most important region in the cerebellum for controlling motor activity, and DCAs alter its signaling in a way that leads to motor symptoms. In conjunction with the implantation of stimulating electrodes, we will also implant recording electrodes in the rats to record from numerous neurons simultaneously. Through these recordings, we hope to determine precisely what elements of neuron signaling directly lead to motor coordination symptoms. This project represents the opportunity to not only prove the concept of a major treatment opportunity for degenerative cerebellar ataxias, but also to greatly enrich our understanding of the neurological changes that directly lead to associated motor symptoms.

PIONEER SCA TRANSITIONAL GRANT AWARDS

Willeke M.C. van Roon-Mom, PhD
Leiden University Medical Center
The Netherlands

Advancing the therapeutic potential of exon skipping for Spinocerebellar ataxia type 3 Spinocerebellar ataxia type 3 (SCA3) is a hereditary form of ataxia where the area of the brain called the cerebellum is most affected. SCA3 is caused by over repetition of CAG sequences in a specific region of the DNA. In healthy individuals, up to 51 repeats of CAG appear, but in people with SCA3, the CAG repeats increase to 51 times or more. Ataxin-3 is an important protein in the brain but becomes toxic with this over repetition of repeats. My team’s research has shown that we can remove specifically the region of the ataxin-3 protein that contains the over repetition by using molecules called antisense oligonucleotides (AONs). In doing so, we are able to directly remove the cause of SCA3 without reducing the amount of ataxin-3 protein. Maintaining ataxin-3 protein levels in the body is key because ataxin-3 seems to be an important protein for normal brain function. When testing the treatment in mice, use of the AONs was well tolerated and effective. To bring the treatment closer to use in patients, we will be further testing the AONs to find the ones that best targets the cause of the SCA3. We will also be testing cultured cells to determine that it is safe to use in humans.

Patrícia Maciel, PhD
University of Minho
Braga, Portugal

Testing the therapeutic potential of Mesenchymal Stem Cells and their secretome in an animal model of spinocerebellar ataxia type 3 Mesenchymal stem cells are cells that come from several tissues, including bone marrow. Research has revealed that these types of cells have a great potential to regenerate damaged organs and tissues. As a result, they are being tested as biological therapy agents against neurodegenerative diseases. Although the effect of the cells has been studied in several neurodegenerative diseases—including ataxias—with promising results, no pre-clinical studies have been done for spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). The goal of this project to study the effectiveness of using either mesenchymal stem cells or biological products derived from these cells to treat SCA3/MJD. For this research, we will evaluate the short-term and long-term effect of these treatments on mice that have SCA3/MJD and have impairments in movement. The tests will measure balance, strength and movement coordination. About 6 months after the stem cells or their biological products have been given to the mice, we will also look at the effectiveness of the treatment in reducing the death of neurons in different areas of the mice’s nervous system. Finally, we will compare different protocols, including different injection sites, to determine which one has a higher effect. In total, the findings of this research should provide important proof-of-concept information for future clinical studies of mesenchymal stem cells in patients with SCA3/MJD.

Harry Orr, PhD
University of Minnesota
Minneapolis, MN

Towards an ASO Therapy for Spinocerebellar Ataxia Type 1 Spinocerebellar ataxia type 1 (SCA1) is a fatal inherited form of ataxia that currently has no effective treatment. Studies using mouse models of SCA1 have shown that reducing expression of the SCA1 gene can reduce SCA1-like symptoms, including dysfunction in movement and premature death. Our team’s research has shown that SCA1 gene expression can be reduced with a drug called an antisense oligonucleotide (ASO). In mice who have SCA1, treatment with an ASO relieved SCA1-like symptoms. Assessing whether therapies are effective in slowing neurodegeneration is difficult using only clinical scales because SCA1 progresses slowly in the body, and it presents in many different ways. Thus, development of additional ways to follow progress of SCA1 might speed moving a drug to clinical trials. To do this, we will use magnetic resonance spectroscopy neuroimaging to examine the brains of the mice before and after they receive the ASO therapy. Our hope is that our research will inform a future pathway for bringing effective ASO therapy to patients with SCA1.

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Upcoming Events

  1. NORD Rare Disease Summit

    October 21 - October 22
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    October 25 - October 27
  3. Western North Carolina Ataxia Support Group Meeting

    October 25 @ 1:00 pm - 3:00 pm
  4. Rare New England Annual Conference

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    October 26 @ 10:00 am - 1:00 pm