Written by: Alexandra (Alexa) Putka
Edited by: Colter Giem
This piece was written in collaboration with the 2025 ComSciCon-MI Write-A-Thon.
In 2019, rare diseases in the United States cost almost $1 trillion in direct and indirect costs to patients and caregivers, according to the National Economic Burden of Rare Disease Study. This astronomical number emphasizes that research on rare diseases not only benefits patients and their families, but it also stands to make a considerable societal and economic impact. I am a graduate student researching a rare genetic disease called Spinocerebellar ataxia type 3, or SCA3, which affects one in every 50,000 to 100,000 people. Ataxia means loss of coordination, and symptoms appear similar to drunkenness: stumbling, falling, incoordination, and slurred speech. Symptoms are relentlessly progressive and result in death, usually 10 to15 years after symptom onset. Unfortunately, SCA3 has no known cures or treatments to halt or reverse disease progression. This emphasizes the need for ongoing research to better understand the disease and provide answers for this fatal disease.
SCA3 is a dominantly inherited disease, meaning if one of your parents has it, you have a 50% chance of having the disease too. The disease-causing gene is called Ataxin-3, or ATXN3. If we could zoom into the genetic code of ATXN3, we would see a repeated series of three nucleotides or code snippets: cytosine, adenine and guanine, or CAG. You can visualize this as a broken printer that keeps spitting out sheets of paper even though you only wanted to print a few. In SCA3, the larger the excess, the more severe the disease. The repeated tract of CAGs is toxic, leading to neuron death in specific brain regions, including the cerebellum and brainstem. Among other functions, the cerebellum is important for motor coordination, while the brainstem controls essential functions like breathing and swallowing. With neurodegeneration impacting these areas of the brain, it is clear how SCA3 severely impacts patients’ quality of life.
But emerging research suggests that it’s not just neurons causing problems in disease, expanding our understanding of the scope of disease and opening the door to new therapeutic targets. My lab’s research focuses on another cell type of the brain called oligodendrocytes. Oligodendrocytes make a fatty coating, called myelin, which wraps around neurons like insulation on a wire to speed up electrical transmission. My lab uses mouse models of SCA3 that are genetically engineered to express the human ATXN3 gene with an expanded CAG repeat, which allows us to better translate our findings to SCA3 in humans. We found a reduction in mature oligodendrocytes in vulnerable brain regions of SCA3 mice, including the cerebellum and brainstem. Like good wine or cheese, oligodendrocytes must mature to fulfill their role as myelin-producing cells. Myelin thickness was also reduced in these mice, which mirrors findings seen in human tissue. Indeed, other labs have shown that alterations to white matter tracts, which include myelin, occur early in disease and correlate with ataxia symptoms in patients with SCA3. While it is clear that oligodendrocytes are dysfunctional in patients with SCA3 and mouse models, we still don’t know why. This is the focus of ongoing research in the lab aiming to tease apart how decreased mature oligodendrocytes and myelin result in the symptoms of SCA3.
For now, we know that research should not focus on neurons as the sole source of disease, as other cells may have a contribution yet to be discovered. This applies far beyond SCA3 to more common neurodegenerative diseases that feature oligodendrocyte alterations, such as Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis, or ALS. By researching these diseases, we can find overlapping pathways of dysfunction that may provide insight into novel therapeutic approaches. Such breakthroughs will not only benefit patients and their families but also society as a whole, given the staggering cost of rare diseases in the U.S.
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