Although we know Purkinje cell dysfunction is central to SCA1, ATXN1 is expressed in nearly every cell type of the body. @Janghoolim and I spent lots of time speculating on what could polyQ ataxin-1 could be doing in other cell populations. We decided to figure it out...
We ran snRNA-seq on the cerebellum of SCA1 knock-in mice throughout all stages of disease progression, as well as on control and SCA1 patient post-mortem tissue. These datasets (over 500k nuclei total) captured the changes in all major cerebellar cell types over time in SCA1 😮
@neal_ravindra, @david_van_dijk, and @chchrislee led the way with the analysis of these data, optimizing methods to enable robust interpretation of disease- and time-dependent changes across all cell types. Lots of iterations to get us to the final datasets, but well worth it 🙃
Too much cool biology in SCA1, but I'll highlight a few of my favorites. Our snRNA-seq data, along with beautiful MERFISH work done by @ChengYubao and @SStevenWang, provide a precise description of synaptic changes between parallel fiber-Purkinje cells throughout disease.
Surprisingly, unipolar brush cells had the most dysregulated gene expression at early stages of diseases (even more than Purkinje cells). Interestingly, these cells are located specifically in the region of the cerebellum that degenerates first in SCA1 🤔🤨
We also see massive changes in oligodendroglial differentiation and myelination, which also appears around the onset of behavioral deficits in SCA1 mice. Veeery interesting but still tbd what these changes mean in terms of overall disease onset/progression.
We have been looking forward to reporting these findings and bringing attention to previously unappreciated cerebellar cell populations in SCA1 and other ataxias. More importantly, we are excited for this to serve as a resource for researchers in the broader ataxia community.
Feel free to reach out with any questions about the datasets, analyses, interpretation, etc. Very happy to chat about SCA1 any day :) Also, please share with anyone who you think might be interested (it's open access 😉).
As you can probably tell, this was a massive collaborative effort across many groups, all bringing different expertise that was necessary for the final product. Thanks to all authors (@neal_ravindra, @chchrislee, @ChengYubao, @billzz_z, @KimLuttik, @LuhanNi9, @Shupei_Zhang, ...
Logan Morrison, John Gionco, @Yangfei_Lab, Jennifer Yoon, @hannahhyewon, Fatema Haidery, Rosa Grijalva, Rose Bae, @kristenkim415, Regina Martuscello, Harry Orr, Huda Zoghbi, @McLoughlinHS, Laura Ranum, Vikram Shakkottai, Phyllis Faust, @SStevenWang, @david_van_dijk, @Janghoolim).
Really thankful for all the reviewers we’ve had for this paper, as well as the editors @CellCellPress @NeuroCellPress, for their thoughtful feedback. The paper has improved tremendously from our first submission, and I’m really proud of the final product.
This project was conceived and developed through coffee chats w/ @Janghoolim at Blue State Coffee ☕️, and discussions related to this project with @LimLabYale, @YaleNeuro, @YaleGenetics, @Yale_INP, and amazing collaborators are some of my fondest memories from graduate school 🫶