One Family's Search to Explain a Fatal Neurological Disorder
With their help, researchers are advancing the 70-year effort to understand—and treat—hereditary ataxia.
Mouse Models of Disease
As medical interest in ataxia grew in the mid-1990s, researchers still had little knowledge about the normal function of the Ataxin-1 gene, let alone how the diseased gene was initiating the neural degeneration that resulted in ataxia and SCA1. To find answers to such challenging questions about the disease, the Orr lab turned to animal models. Our team identified a related gene in mice that we named Sca1.
Mouse Sca1 and human ATXN1 are strikingly similar; however, the mouse gene contains only two CAG repeats. To mimic the human disease in the mouse model, we created a transgenic mouse that expressed the human ATXN1 gene with 82 CAG repeats. Eighty-two was the highest number of repeats observed in a human SCA1 patient, and this individual experienced disease onset when younger than five years old. As seen in human SCA1 patients, transgenic mice with 82 CAG repeats had progressive ataxia and degeneration of the Purkinje cells.
The mice proved to be an excellent model system to study the disease, and they allowed us a closer look at what might cause cell death. We observed clumps of proteins called aggregates forming within the Purkinje cells of diseased animals. It made sense to conclude that the aggregates forming in the nucleus were toxic and resulted in cell death. However, questions remained about what, if anything, these aggregates were doing. Were the aggregates causing the disease, or were they a result of it? Was the expanded Ataxin-1 protein clumping together to form aggregates, or was another protein?
To get some answers to these questions, in 1998 we generated another transgenic mouse model that expressed the expanded human ATXN1 gene, but with an added mutation that prevented it from interacting with itself and forming aggregates. We discovered that mice with this mutation still developed ataxia and underwent Purkinje cell death, but they did not form aggregates in their Purkinje cells. The finding showed that aggregates were not the cause of cell death and disease.
That same year, we also created a mouse completely lacking the normal Sca1 gene to study loss of Ataxin-1 function. These mice did not develop ataxia or have any Purkinje cell death, which indicated that the mutation in Ataxin-1 was not causing a nonfunctional protein. However, mutant Ataxin-1 was doing something to instigate the disease.
Ataxin-1 is normally located in both the cytoplasm and the nucleus of Purkinje cells. We next discovered that Ataxin-1 had to enter the cell nucleus to cause disease. Once it entered the nucleus, the expanded Ataxin-1 protein had difficulty transporting back out. If we kept Ataxin-1 out of the nucleus, we could potentially halt progression of the disease. This seemed like a simple task, but again we faced another hurdle: We did not know what controlled Ataxin-1's entrance into the nucleus. We knew there could be other genes or factors involved in regulating Ataxin-1. And we were unsure what the mutant protein did to cause disease once it was in the nucleus. The list of unknowns was getting longer, not shorter.
Researchers quickly appreciated the complexity of the disorder and our limited understanding of the disease. Undeterred by the challenge, the field of ataxia research continued growing quickly. Each research team tackled different critical questions about the disease. We are still asking these and many other questions. We are not certain whether the mutant Ataxin-1 protein retains much of its normal function, or whether it develops entirely new functions. The complexity of Ataxin-1 biology makes development of a cure slow going.
Our lab, along with Zohgbi's lab, is carrying out high-throughput screens, a current method for rapidly identifying important compounds in a biochemical pathway, to find molecules that reduce the levels of Ataxin-1 protein. We also are investigating the effects of modifying the Ataxin-1 protein and the implications for its biological activity. For example, like many enzymes, Ataxin-1 is turned "on" or "off" depending on whether a phosphate group is added to it or not, which regulates its interaction with other molecules that block Ataxin-1 from entering the nucleus. By suppressing the activities of proteins responsible for adding a phosphate group to Ataxin-1, we may be able to improve the condition of the cerebellar Purkinje cells and reduce the severity of ataxia. We are conducting these studies in mouse models, and we still have much to accomplish before a potential treatment for SCA1 could go through clinical trials in humans.
Understanding the biology behind SCA1 will spur drug discovery and progress in research of other related neurodegenerative disorders. Therefore, the fight of one family struggling with this rare disorder is also affecting other areas of disease research.
Ataxia in Future Generations
Because the family has received genetic counseling, Schut family reunions are no longer opportunities to collect blood samples for genetic testing; instead, they can focus on food and socializing, just as other families do. Only one family member is currently affected by the disease, and another is untested for ataxia and under the age of eighteen. Larry Schut continues to work as a neurologist and to have an interest in a variety of newly identified forms of spinocerebellar ataxia. The family remains active with the National Ataxia Foundation, which in contrast to its humble beginnings, today spends over $1 million annually to support ataxia research.
Despite all these advances, there are currently no clinical-stage treatments for hereditary and sporadic ataxias, and there is still only limited public awareness about the disease. Even in families where hereditary ataxia has presented in multiple generations, patients may struggle for an accurate diagnosis because the disease can be mistaken for other movement disorders, such as multiple sclerosis or amyotrophic lateral sclerosis. Educating the public and providing support for patients affected by ataxia is a major goal of the National Ataxia Foundation.
SCA1 remains at large in other families across the United States, including hundreds of at-risk individuals who may pass the disorder along to their children. Thankfully, the fate for these families is much better than what was faced a century ago, or even 50 years ago. Families have a genetic test for the disease, and government assistance provides help for those affected by this debilitating disorder. Researchers continue to progress toward the next breakthrough to understanding this disease. Decades of dedication from patients, families, and the research community brought scientists closer to understanding hereditary forms of ataxia and identifying a treatment for the disease.
One of us (Nissa Mollema) began researching ataxia after finishing her Ph.D. in 2010 and joining the Orr lab shortly thereafter. Only a few months into the job, a conversation with her mother-in-law led her to discover that perhaps something beyond scientific interest had directed her to find a place in ataxia research. Mollema learned that her husband's great-grandmother had seven siblings affected by SCA1, and that one of these siblings was Henry and John Schut's father.
Reflecting on the early days of ataxia research, Mollema was struck by how the discoveries that paved the way for her research were driven by a simple desire to improve life for the next generation and to prevent the suffering the current generation faced. Questions about SCA1 and a host of related neurodegenerative diseases remain, but collaboration and determination continue to advance our understanding of the larger scientific puzzle.
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