A collaborative study led by Yale researchers reports the many gene expression changes that develop over the course of a neurodegenerative disorder called spinocerebellar ataxia type 1, shedding light on its progression. Spinocerebellar ataxia type 1 is a disorder that mainly affects the cerebellum, a brain region involved in motor coordination. With time, patients lose their ability to walk properly. Most studies of ataxia focus on Purkinje cells, a cell type in the cerebellum that eventually degenerate and die. However, many other cell types co-exist in the cerebellum, and their involvement in ataxia is unknown. Historically, it has been hard to study them, mostly because of their relative low abundance: to detect their role in a sea of other cells, a cutting-edge, single-cell approach was needed. In a new study published in Neuron on November 27, the Lim lab and collaborators showed that many different cell types are affected by the disease by using a technique called single-nucleus RNA sequencing, which allowed them to observe gene expression changes at the level of individual cells. Until now, researchers have looked at the cerebellum at the very end of the disease progression. But what leads to the final stage? "Here, we catalog how different cell types are affected from early to late stages of the disease" said Leon Tejwani, PhD, former graduate student in Yale’s Interdepartmental Neuroscience Program and co-first author of the study. The longitudinal study revealed important dysfunctions for previously unappreciated cerebellar cell types in ataxia. The team applied a deep learning method to predict if cells were healthy or not. With this approach, the team was not only able to detect the cells that exhibit early signs of the disease in the cerebellum, but also identify the gene expression patterns used by the model to make predictions. The Yale researchers are the first to study gene expression changes in post-mortem tissues of patients with ataxia at a single-cell resolution. Tejwani emphasized how crucial the many collaborations (within Yale and beyond) were to overcome the limitations, from human post-mortem tissue collection to single-cell RNA sequencing analysis. Our study describes what's going wrong in all cell types of the cerebellum over the course of the disease, and studying the exact implications of these dysfunctions - and their overall contributions to the disease - will be the next step.Leon Tejwani, PhD While being cautiously conservative for clinical implications, the team thinks this study will accelerate research in the field of ataxia by being a resource for labs around the world. The findings were published in November 27 in the journal Neuron. The publication has four first-authors across 3 Yale departments: Leon Tejwani, PhD, Neal G Ravindra, PhD, Changwoo Lee, & Yubao Cheng, and four corresponding authors: Leon Tejwani, PhD, Siyuan Wang, PhD, associate professor of Genetics and Cell Biology, David van Dijk, PhD, assistant professor of Medicine and of Computer Science, & Janghoo Lim, PhD, associate professor of Neuroscience and Genetics.