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Your Dollars At Work:

A Look at NAF Funded Research

NAF provided funding for 20 Ataxia research studies for fiscal year 2016. A summary of the completed research studies was published in Generations.

Research Grant

Perlman, Susan, M.D.
University of California
Los Angeles, CA

Web-based National Ataxia Database The National Ataxia Registry (PI-Dr. S. Subramony; now supported by the CORDS registry), the National Ataxia Database (PI-Dr. S. Perlman), and the Ataxia Tissue Donation Program (PI-Dr. A Koeppen; now supported at individual sites) have formed the infrastructure for clinical research in the ataxic disorders. They enable 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. Four prior National Ataxia Foundation grants (1/1/01-12/13/01; 01/01/04-12/31/14, 1/1/05-12/31/05, 1/1/07-12/31/07) were used to develop the web-based, National Ataxia Database. It 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 "ataxologists" 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. It is also a safe and permanent repository for clinical research data that has already been collected. The templates for the Rare Disease Network-supported CRC-SCA natural history study (PI-T. Ashizawa) are now part of the National Ataxia Database. Following the end of funding of that project, with the help of the NAF "bridge" grants for the Web-based National Ataxia Database (1/1/14-12/31/15), we were able to continue to import the existing coded data of the natural history study into the National Ataxia Database, to enable continued enrollment and follow-up of subjects in this important study of SCA 1, 2, 3, and 6. There are now 13 registered sites contributing to this project. Over 400 subjects have been enrolled and are pursing serial examinations and banking of specimens. 5 have already resulted from this resource. 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.


Paul Rosenberg, M.D.
Duke University Medical Center
Durham, NC

Contribution of store-operated calcium entry to calcium dysregulation in spinocerebellar ataxias The ataxias are a heterogeneous group of disorders that result from degeneration of the cerebellum and its connections to other brain regions. The cerebellum is involved in motor coordination and learning and cerebellar Purkinje neurons play a central role in these processes. Dysregulation of neuronal calcium signaling has emerged as a common feature underlying the dysfunction, degeneration, and death of Purkinje neurons in a number of ataxias, including the hereditary spinocerebellar ataxias. Understanding the mechanisms that mediate calcium dysregulation in this diverse group of diseases is essential for understanding the pathogenesis of these ataxias and for developing effective therapeutic strategies to treat this debilitating group of diseases. Recent studies have established the importance of a novel calcium signaling pathway know as store-operated calcium entry (SOCE), which requires the STIM1 calcium sensor, in regulating the calcium dynamics of Purkinje cells and other neurons. While a number of calcium signaling pathways have been implicated in the dysregulation of calcium homeostasis and pathogenesis of ataxia, the possibility that SOCE is involved has not been investigated. The goal of this proposal is thus to determine the role of STIM1-dependent SOCE in the disturbances of calcium handling in ataxias. Our central hypothesis is that disruption of STIM1-dependent SOCE makes a critical contribution to Purkinje cell dysfunction and degeneration and consequent functional deficits in several types of ataxia. To test this hypothesis we will first investigate whether SOCE contributes to the dysregulation of calcium homeostasis and Purkinje cell dysfunction in established mouse models for several of the ataxias. Second, we will determine the extent to which an increase or decrease in STIM1-dependent calcium signaling might account for Purkinje cell dysfunction and degeneration in ataxia. These studies will begin to elucidate the role of SOCE in calcium-dependent Purkinje cell degeneration in ataxia and may ultimately lead to novel therapeutic options for treating for these degenerative disorders.

Mendonça Simões, Liliana, PharmD, Ph.D.
University of Coimbra

The transplantation of induced pluripotent stem cells (IPSC)-derived neural stem cells (NSC) in Machado Joseph disease (MJD) Machado-Joseph disease (MJD) is a progressive and frequently fatal neurodegenerative disease, originally described in people of Portuguese descent, and caused by a mutation on the ATXN3 gene that originates a mutant ataxin-3 protein. Mutant ataxin-3 protein is toxic causing neuronal dysfunction and degeneration in specific brain regions and leading to motor and non-motor symptoms. Although there is no effective treatment for this disease some specific molecular strategies such as gene silencing of mutant ATXN3 resulted in promising outcomes. However, the translation of these therapeutic strategies into clinical application is most probable in symptomatic patients, already with extensive neuronal loss, and therefore we consider that cell replacement will also be needed. Recently, we demonstrated that cerebellar transplantation of NSC isolated from newborn mice into the cerebellum of adult MJD mice increase neurotrophic factors levels, reduce neuro-inflammation and neuronal loss and trigger a significant and robust improvement of the MJD-associated motor coordination impairments. Moreover, we observed that the transplanted NSC differentiate into neural cells. However, the lack of reliable human NSC sources is a big drawback in the implementation of NSC transplantation in clinical practice. One way to overcome the lack of human NSC sources is to use differentiated cells of the patients that can be reprogrammed to IPSC. Then, IPSC can be induced into NSC and subsequently the mutant ATXN3 mRNA can be silenced. Therefore, we speculate that it is possible to generate patient-specific NSC depleted of the mutation responsible for the disease. Moreover, we hypothesize that the transplantation of mutant ataxin-3 depleted patient-derived NSC can be used for neuroregeneration of brain lesions of MJD patients promoting functional recovery. Therefore, the specific aims of this project are: 1) to generate mutant ataxin-3-depleted NSC from fibroblasts of MJD-patients and 2) to evaluate if the transplantation of mutant ataxin-3 depleted patient-derived NSC in MJD-transgenic mice leads to improvement in MJD-associated neuropathology and motor phenotype impairments.

Fogel, Brent L., M.D., Ph.D.
University of California
Los Angeles, CA

Development of a Cellular Model for the Functional Characterization of SCA41 Mutations Neurons in the human brain communicate information with one another, enabling coordinated function and protection from injury due to metabolic stress. This communication occurs through receptors, or channels, on the cell surface that recognize small molecules. One such channel is named TRPC3 and it transports positively charged ions to communicate signals within the cell. In mice, mutation of Trpc3 leads to cerebellar ataxia and affects critical pathways important in cerebellar function. TRPC3 is also expressed in the human cerebellum and recently we reported a sporadic ataxia patient with a suspected TRPC3 mutation (p.R762H) predicated to impair the function of this channel. We demonstrated that the human p.R762H mutation behaves like the ataxia-causing mutation in mice and therefore causes disease. This new form of dominant cerebellar ataxia was named Spinocerebellar Ataxia, type 41 (SCA41). The identification of the first patient with SCA41 has raised many questions about this new disease. We propose to investigate SCA41 by 1) developing a human cellular model system to study TRPC3 and characterize its mutations, and 2) broadly evaluate a large population of sporadic and dominant ataxia patients for TRPC3 mutations to better understand the clinical presentation and frequency of this disease. Specific Aim 1) We will create cell lines, termed induced pluripotent stem cells (iPSCs), from normal and SCA41 patient skin cells that can be differentiated into cerebellar neurons and used to model the function of the human cerebellum in a dish. 1A) The effects of the p.R762H SCA41 mutation will be studied through a series of physiological tests to determine which aspects of channel function are working correctly or not. 1B) Suspected mutations identified in Specific Aim 2 will be tested by developing iPSCs from these patient’s skin cells. We have already found one potential patient to study. 1C) Additional mutations, including the known ataxia mutations in mice, will also be tested by introducing them directly into normal human iPSC cell lines using a method called genome editing. Ultimately, we will be able to study every key region of the protein to predict which changes are likely to cause ataxia in people to improve the diagnosis of future patients. This model system will also provide a means of testing new channel-modifying drug therapies. Specific Aim 2) To identify new mutations in TRPC3 we plan to evaluate our extensive patient population for changes in the gene. Using a combination of exome sequencing and targeted gene resequencing we will examine undiagnosed dominant families and patients with sporadic ataxia for rare or novel sequence changes in TRPC3. By comparing the potential effects of these rare changes to more common changes found in normal individuals, we can estimate whether these are likely to be mutations that may cause ataxia and test them in Specific Aim 1B to see if they damage channel function. This may also help us devise new ways to verify novel mutations in other ataxia genes as well.

Fanto, Manolis, Ph.D.
King’s College
London Great Britain

Rbfox proteins as critical determinants for cell toxicity in DRPLA and other Spinocerebellar Ataxias Dentatorubropallidoluysian-Atrophy (DRPLA) is a genetically inherited form of Ataxia. Whereas all cells in the brain express the diseased gene, some brain areas, are more sensitive to its expression and degenerate earlier. We have identified one protein family, whose expression is different precisely in these brain areas in a mouse model for the disease. We are now planning a series of experiments to verify if this protein, and those closely related to it, are indeed important in sensitizing the neurons to the DRPLA gene. If this is the case, this will be a first step towards devising a therapeutical strategy that aims at protecting these brain areas more substantially than others to delay the disease onset.

Downey, Michael, Ph.D.
University of Ottawa
Ontario, Canada

A new look at Ataxia7 as a regulator of substrate selection by the KAT2a acetyltransferase Spinocerebellar ataxia type 7 (SCA7) is an inherited disease that affects a type of cell in the body called a neuron, which are found in the brain and help us to sense the environment around us. SCA7 patients have difficulty walking and talking. In addition, they experience a deterioration in vision and may even become blind as they grow older. At the heart of SCA7 is a protein called Ataxin7. All proteins are made of individual building blocks called amino acids and the order and number of these amino acids dictates what they do in the cell. SCA7 patients produce Ataxin7 that has extra amino acids. The reason these extra amino acids cause problems for affected individuals is unknown. Our proposed project uses cutting-edge protein analysis tools, including a very sensitive instrument called a mass spectrometer, to investigate the idea that these extra amino acids change the way the Ataxin7 physically interacts with other proteins in the cell, preventing them from carrying out their jobs. Our creative approach to studying SCA7 has the potential to uncover drug targets that can be exploited to prevent the death of neurons in patients and stave off symptoms of the disease.

Aquilano, Katie, Ph.D.
University of Rome Tor Vergata
Rome, Italy

Study of the role of lipid dysmetabolism in the pathogenesis of Friedreich’s ataxia Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease caused by mutations in the mitochondrial protein frataxin (FRX). Complications of FRDA include diabetes mellitus and cardiomyopathy. Understanding the molecular links between FRX mutation and development of metabolic disturbance is of pivotal importance for finding new therapeutic strategies to ameliorate disease’s symptoms. By using a mouse model of FRDA, we want to assess whether accumulation of intracellular lipids in the form of lipid droplets (LDs) and impairment of lipid degradation could be operative in heart and brain. We also intend to test whether such events can be ascribed to the decrease of the content of cellular lipases such as adipose triglyceride lipase (ATGL) and lysosomal lipase (Lipa). Finally, in this research project we aim at identifying the impairment of lipase downstream lipid signaling as a crucial factor in mitochondrial metabolic dysfunction in FRDA. Our research could therefore give effort in developing new therapeutic approaches and druggable targets to overwhelm cardiomyopathy and neurodegeneration that could be exploited for future clinical research.


Tumbale, Percy, Ph.D.
National Institute of Environmental Health Sciences, National Institutes of Health
Research Triangle Park, NC

Expanded Roles for Aprataxin Mutations in Ataxia Oculomotor Apraxia 1 (AOA1) Ataxia Oculomotor Apraxia 1 (AOA1) is an autosomal recessive ataxia which resembles Friedreich’s Ataxia (FA) and Ataxia-Telangiectasia (A-T) but without the extra-neurological features. The clinical characteristics of AOA1 are difficulty coordinating movements (ataxia), impaired initiation of saccadic eye movement (oculomotor apraxia), and neuropathy. AOA1 symptoms typically manifest in early childhood, with slow progression until patients become wheelchair-bound within a decade of onset. Currently, there is no treatment to improve or prevent the progression of this disease. AOA1 is caused by mutations in the aprataxin gene (APTX), encoding the protein aprataxin (Aptx). Aptx plays a crucial role in DNA repair, and acts as the proofreader for DNA ligases. Although a wealth of evidence supports a role for Aptx in nuclear DNA repair, it is not known whether that is the only function of Aptx. Aptx localizes to the nucleus and nucleolus, pointing to roles in these organelles. Our data have shown many AOA1-linked Aptx mutations that cause severe symptoms in patients have only a minor impact on Aptx activity. Moreover, Aptx is ubiquitously expressed in human tissues but specifically associated with a neuronal disease, suggesting Aptx mutations may cause AOA1 in patients by other unknown mechanisms. In agreement with this, we have identified an AOA1-linked Aptx mutation that abolishes Aptx nucleolar localization, yet only moderately impairs Aptx activity. Our data point to an extended role for Aptx in the nucleolus. Here we present a research proposal aiming to delineate the links between Aptx nucleolar dysfunction and AOA1. Hypothesis 1: Aptx plays important roles in the nucleolus, and its nucleolar localization is mediated by nucleolar proteins. Hypothesis 2: AOA1-linked Aptx mutations impair Aptx interactions with nucleolar proteins, resulting in loss of Aptx in the nucleolus. Thus, Aptx nucleolar dysfunction is among the causes that contribute to AOA1. Aim 1: Define the molecular mechanism and regulation of Aptx nucleolar localization mediated by its interacting nucleolar proteins, Aim 2: Define the nucleolar functions of Aptx, and how AOA1-linked Aptx mutations impact Aptx nucleolar functions. The studies here explore biological functions of Aptx beyond the presently understood role in nuclear DNA repair. We will establish a molecular platform to explore new links between APTX dysfunction and AOA1. We believe this will lead to development of better strategies to effectively diagnose, monitor, and possibly prevent AOA1 progression.

Tsou, Wei-Ling, Ph.D.
Wayne State University School of Medicine

Mechanisms of Neuroprotection by DnaJ-1 in Spinocerebellar Ataxia Type 6 Spinocerebellar Ataxia Type 6 (SCA6) is a type of dominantly inherited ataxia that impacts overall motility and can also present with impaired eye movements. There are currently no treatments that are effective in the clinic for SCA6. In an effort to identify viable options for SCA6 therapy, we recently generated transgenic fruit flies that express the toxic protein in this disease. Through various experimental approaches, we found proteins that ameliorate SCA6-like toxicity in intact animals. Here, we propose to determine the mechanism of neuroprotection in this model of SCA6, with the hope to target it for therapy in the near future.

Scaglione, Kenneth Matthew, Ph.D.
Medical College of Wisconsin
Milwaukee, WI

Investigation into polyglutamine in Dictyostelium Two of the three major genetic categories of the Spinocerebellar ataxias (SCAs) are caused by the presence of repetitive genetic elements. Many of these repetitive genetic elements are made into proteins and result in the formation of toxic clumps of protein. Investigation of how these clumps of protein cause toxicity is typically performed by introducing these proteins into model organisms where they recapitulate the toxic features observed in human disease. We observed that one organism normally makes proteins that share similarity to the ones that clump in human disease. We have also observed that this organism is resistant to clumping of human proteins that are known to clump in other diseases. Our goal is to understand how this organism resists protein clumping, and see if we can translate that finding to treat human disease.

Richard, Patricia, Ph.D.
University of British Columbia
New York, NY

Role of the SETX/CHD3 interaction in the DNA damage response and its connection to AOA2 Neurological diseases are disorders of the brain, spinal cord and nerves that control the body. Ataxia Oculomotor Apraxia type 2 (AOA2) is a clinical manifestation of the dysfunction of parts of the nervous system (the cerebellum) that coordinate movement and leads to severe motor handicap. AOA2 is a frequent type of autosomal degenerative cerebellar ataxia and is caused by mutations in the Senataxin (SETX) gene. SETX has been shown to be involved in the response to DNA damage. We recently found that SETX can associate with CHD3, a component of a complex that is able to compact DNA. Compaction/relaxation of chromatin plays an important role in the DNA damage response. After DNA damage, compacted chromatin needs to be relaxed to allow the DNA repair machinery to access to the damage. We found that several AOA2 mutations in SETX can disrupt the interaction. But considerable additional work is required to understand fully the significance of these findings, and how they can be exploited to combat AOA2. My studies are aimed at dissecting how the SETX/CHD3 interaction affects the process of DNA damage repair and, importantly, leads to AOA2 disease when defective. By using biochemical and molecular biology approaches, I will investigate the function of SETX and CHD3 in response to DNA damage, and how AOA2 mutations disrupt this process. A fuller understanding of the molecular function of the SETX/CHD3 complex in chromatin remodeling and the DNA damage response will lead to a better understanding of ataxia, and ultimately to novel therapeutic approaches to prevent and treat the disease.

Pinto, Ricardo Mouro, Ph.D.
Massachusetts General Hospital Harvard Medical School
Boston, MA

Identification of genetic modifiers of somatic GAA instability in Friedreich Ataxia by in vivo CRISPR-Cas9 genome editing Friedreich's ataxia (FA) is a devastating neurodegenerative disorder for which there is no cure or significant disease-modifying treatment. It is caused by a rare genetic mutation that results in lower levels of an important protein – frataxin – being produced. The most common mutation consists of an expanded stretch of repetitive DNA in the frataxin gene – GAA trinucleotide repeat. The longer the GAA repeat, the less frataxin protein is produced. In addition to being expanded in FA patients, this repeat has a strong tendency for further expanding, not only in transmissions from parent to child, but also throughout the life of the patient, particularly in organs primarily affected in FA. This raises the hypothesis that this process can accelerate the onset and progression of the disease in FA patients. To date, we have already learned that genes involved in maintaining the integrity of our genomes throughout the life of a cell (DNA repair genes) are involved in the GAA expansion mechanism. However, we still have a very limited understanding of how this process occurs. Knowing the key players and understanding this mechanisms in much more detail is very important since it should facilitate the development of therapeutics that target the mutation directly. In addition, a recent study that looked at ~4050 Huntington’s Disease (HD) patients (also caused by a trinucleotide repeat) revealed that genes involved in various DNA repair pathways are likely modifiers of HD age of onset, further echoing the potential therapeutic impact of targeting these genes. Our goal, is to use novel genome editing strategies in FA mouse models, namely the CRISPR-Cas9 toolbox, to determine if these genes are involved in the GAA repeat expansion process and whether they modify FA-related symptoms.

Grasselli, Giorgio, Ph.D.
The University of Chicago
Chicago, IL

Role of SK channels in cerebellar Purkinje cells in the Pathophysiology of spinocerebellar ataxia Recent promising results for the treatment of ataxia have been obtained in mouse models as well as in pilot clinical trials with drugs enhancing the activity of a type of potassium channels named SK. These channels are able to lower the excitability of the neuron and decrease the variability of its spike firing and regulate its spike patterns. However, it is still largely unclear what role is played by SK channels in preventing ataxic symptoms and, more in general, the impairments in the neuronal circuit of the cerebellum that cause these symptoms. We propose to clarify the role of SK channels specifically expressed in the major type of neurons in the cerebellum (Purkinje cells, PC), responsible for the sole output of cerebellar cortex. We will investigate in particular the role played by SK channels in these neurons in the generation of motor impairments and in the generation of neuronal electrical output of PC. To do this we will use a new mutant mouse that will be soon available in our laboratory, lacking SK channels specifically in PC (a PC-specific SK2 knockout mouse). We will analyze the gait of these mice, in order to determine whether SK channels in PC play a major role in the generation of ataxic symptoms and whether PC are the major targets of drugs enhancing the activity of SK channels. Moreover we will analyze the major features of PC electrical output that are regulated by SK channels (spiking variability and spiking pauses). Finally we will identify common features in other models of ataxia for the components of gait control and PC physiology. We will use a mouse lacking completely SK channels (constitutive SK2 knock-out) and a mouse lacking the calcium channels responsible for SCA6 (CACNA1A knockout) and partially rescued for the expression of the fragment of this protein, shown to have an independent function as a transcription factor. In this way we will isolate the role played by the channel from the role played by the transcription factor. This proposal will pave the way to a mechanistic understanding of the role of SK channels in spinocerebellar ataxia and to the design of more effective therapeutic strategies for this disorder.

Goetz, Sarah, Ph.D.
Duke University
Durham, NC

Exploring the Role of Primary Cilia in SCA11 Pathogenesis My lab studies primary cilia- tiny projections that resemble antennae and are found on most cells. Like antennae, cilia function to receive certain types of signals from neighboring cells and help to coordinate a response. Cilia are therefore very important during embryonic development, and genetic disruptions of cilia cause a variety of heritable developmental disorders. In my prior work, I identified a protein, TTBK2, that plays a unique role in controlling the assembly of cilia. The gene that encodes this protein was also separately found to be mutated in SCA11. Three different SCA11-associated mutations all produce a nearly identical truncated form of TTBK2. The goals of my research are to examine how this truncated protein is causing degeneration of the cerebellum. We will test whether and how these truncations interfere with the function of the normal TTBK2 protein in cilia formation. We will also test whether reducing the function of TTBK2 or losing cilia within the adult cerebellum can cause degeneration of that tissue and ataxia, using mutant mice as a model. Though this proposed work we hope to gain a better understanding of the molecular mechanisms that cause SCA11-associated pathology as well as to define a novel role for primary cilia-based signaling in maintaining neural function in the adult brain.


Yang, Su, Ph.D.
Emory University
Atlanta, GA

Developing the MANF-based therapeutic approach for Spinocerebellar Ataxia 17 Spinocerebellar Ataxia 17 (SCA17) is a progressive neurodegenerative disease that is genetically inherited. The cause of SCA17 is a specific mutation in the gene encoding a protein named TATA box binding protein (TBP), which makes TBP become misfolded and toxic. SCA17 is characterized by prominent neuronal loss in the cerebellum, and patients display a broad spectrum of symptoms, including ataxia, parkinsonism, dementia and psychiatric abnormalities. There is currently no effective treatment for this devastating disease. In our previous study, we identified a protein named mesencephalic astrocyte-derived neurotrophic factor (MANF), whose expression level is reduced in the cerebellum of a mouse model of SCA17. Increasing the amount of MANF in that mouse model ameliorated SCA17 disease phenotypes. MANF is also known to be neuroprotective in other disease conditions including Parkinson's disease and ischemic stroke. These facts suggest that MANF could be a therapeutic target for the treatment of SCA17. Our research is aimed at developing MANF-based therapeutic approach for SCA17. We have screened a collection of 2000 US Food and Drug Administration (FDA) approved compounds and natural products, and found several compounds that can stimulate MANF expression in cultured cells. We will continue to test if these compounds can manage SCA17 disease phenotypes when given to our SCA17 mouse model. The result of our study would have an immediate impact on the development of SCA17 treatment, as the compounds to be tested are already FDA approved. Furthermore, as cerebellum degeneration is common among other SCA types, the MANF-based therapeutic approach could have broad implications for the treatments of other SCA types as well.

Singh, Pankaj Kumar, Ph.D.
Institut De Génétique Et De Biologie Moléculaire

Unravelling pathomechanisms of muscle dysfunction in an autosomal recessive cerebellar ataxia 2 (ARCA2) mice model Mutation in AarF Domain Containing Kinase 3 (ADCK3) gene leads to autosomal recessive cerebellar ataxia 2 (ARCA2). The prevalent features of the disease include ataxia, cerebellar atrophy, ubiquinone deficiency in muscle and exercise intolerance. The pathogenic protein ADCK3, is a putative mitochondrial kinase and based on its homology with yeast CoQ8 proteins, is proposed to have an undefined role in the biosynthesis of small lipid coenzyme Q (CoQ). Our recently created constitutive Adck3 knockout mice (Adck3KO) recapitulate many pathogenic features of the disease, including ataxia, CoQ deficit in the skeletal muscle and mild exercise intolerance. Further careful investigation of pathogenic changes in these mice reveals a mitochondrial defect specifically in the skeletal muscle. Mitochondria are dynamic organelle involved in oxidative respiration and energy production and lie at the center of cellular growth and metabolism. Mitochondrial diseases due to defects in respiratory chain complexes and consequent impartments in the electron transport chain are quite prevalent. These diseases have mild to severe pathological consequences depending upon the extent of dysregulation in mitochondrial performance and metabolic harmony. Exercise intolerance is one such consequence of compromised mitochondrial activity, caused due to reduced oxygen consumption and increased anaerobic metabolism in the skeletal muscle. Exercise intolerance seen in ARCA2 patients and in Adck3KO mice could thus be a consequence of defective mitochondrial function and metabolic homeostasis in the skeletal muscle. This proposal therefore, intends to uncover the fundamental basis of mitochondrial/metabolic perturbation in the skeletal muscle of Adck3KO mice. Our emphasis will be to identify a molecular target, which can be modulated in the skeletal muscle to improve respiratory performance and alleviate physiological irregularities including exercise intolerance in Adck3KO mice. Moreover, cellular pathways and molecules affected upon ADCK3 deficiency in muscle can further be targeted in the cerebellum to investigate if they could also underlie cerebellar dysfunction and ataxia in ARCA2. Together, delineating the underlying basis of skeletal muscle dysfunction in ARCA2, this study will help finding a potential therapeutic target for the disease.

Santana, Magda Matos, PharmD, Ph.D.
Center for Neuroscience and Cell Biology
Coimbra, Portugal

Advanced Induced Pluripotent Stem Cell-based Models of Machado-Joseph disease Machado–Joseph disease (MJD), or spinocerebellar ataxia type 3, is a neurodegenerative polyQ disease and the most common of the dominantly inherited ataxias worldwide. Despite important progresses in the knowledge of the pathological mechanisms involved we still miss effective therapies. Advances in this field depend on innovative and predictive models of disease for which there is an urgent need for both mechanistic and preclinical studies. Among such models, the induced pluripotent stem cells (iPSC) are the leading tools, offering the promise of enabling major ground-breaking advances. Disease-specific stem cells and the resulting differentiated cell types offer an unprecedented opportunity to investigate the molecular mechanisms and to perform preclinical drug screening. Nevertheless, the use of these cells and their differentiated derivatives still present challenges due to line-to-line variations, experiment–to-experiment differentiation variations and genetic instability. To overcome these issues, identify and later easily assess typical signatures associated with disease mutations, we will produce isogenic patient-specific lines and differentiate these cells into mature cerebellar neurons from MJD patients-derived iPSCs and isogenic controls. This will allow the genetic determinant to be challenged in strictly identical cells that not differ in any way in terms of their genome. We will further use these cells to develop and implement standardized, robust medium/high throughput methodologies for quantitative analysis of specific defects to investigate pathomechanisms and drug screening in MJD. We expect this project can make a truly important contribution to the field of ataxias and particularly of Machado-Joseph disease by providing the models and methodologies to enable significant advances in the knowledge of the mechanisms of MJD and provide the tools for pre-clinical identification and validation of new effective therapies for MJD.

Cohen, Rachael L., DVM
Johns Hopkins University School of Medicine
Baltimore, MD

Molecular Pathogenesis of Spinocerebellar Ataxia Type 12 Spinocerebellar ataxia type 12 (SCA12) is a rare progressive autosomal dominant neurodegenerative disease. SCA12 is caused by a CAG trinucleotide repeat expansion.


Raskind, Wendy H., M.D., Ph.D.
University of Washington
Seattle, WA

Oligonucleotide-based Therapy in BAC-Mouse Models of SCA14 SCA14 is one of the autosomal dominant spinocerebellar ataxias that are not caused by expansion of a DNA repeat sequence. It is a typical SCA and like others, there is no treatment to prevent, stop or slow its progression. We previously discovered that SCA14 is caused by mutations in the gene for the enzyme protein kinase C gamma (PKC?). We created transgenic mouse lines that carry the normal human PKC? gene or one of two SCA14-associated mutated forms, along with the gene’s normal regulatory information. In these lines human PKC? is made in the central nervous system everywhere it should be and at the correct times in development. The PKC? protein that contains one of the mutations forms large aggregates in cerebellar Purkinje cells. The other mutation causes Purkinje cells to develop abnormal dendrites. Dendrites are nerve cell processes that receive signals from other nerve cells. Mutant PKC? protein is toxic to cells, but the normal human one is not. Mice that have only one working copy of the mouse PKC? gene do not develop Purkinje cell abnormalities and appear neurologically normal. Established and investigational treatments for other diseases provide reasons to be encouraged about the possibility to develop targeted treatment for SCA14. In cancers where abnormal protein kinases play a role, medications that block the kinase are being used successfully to treat patients. Short nucleotide sequences that suppress or alter the mutant gene are being studied in patients with other inherited neurodegenerative disorders. Therefore, we propose to study the effect of suppressing production of the abnormal human PKC? protein on the cerebellar abnormalities that develop in the mutant transgenic mice. The experiments we propose are a first step towards identification and study of therapeutic agents in patients with SCA14.

Ranum, Laura, Ph.D.
University of Florida
Gainesville, FL

ASO targeting of bidirectional transcripts and RAN translation in SCA8 The spinocerebellar ataxias are often caused by repeat expansion mutations in which repetitive stretches of three or more letters of the genetic code are repeated extra times. The genetic mutation is found in families with a dominant history of disease but also frequently appears in individuals with no family history as a “sporadic” form of ataxia. Through our work on SCA8, we have discovered that expansion mutations can be expressed in both directions and that the resulting CUG and CAG expansion RNAs can direct the production of an unexpected category of mutant proteins without the normal regulatory signals. Our goal is to understand how these mutant RNAs and proteins contribute to disease and to develop therapeutic strategies to block their effects.


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