임장후 (Yale School of Medicine)

한빛사논문

조회241

Yale School of Medicine

Neuron, November 27, 2023 | https://doi.org/10.1016/j.neuron.2023.10.039 Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1

Leon Tejwani,^1,2,23,24,* Neal G. Ravindra,^3,4,23,25 Changwoo Lee,^1,2,23 Yubao Cheng,^5,23 Billy Nguyen,⁶ Kimberly Luttik,^1,2 Luhan Ni,⁵ Shupei Zhang,⁵ Logan M. Morrison,^7,8 John Gionco,⁹Yangfei Xiang,^5,10,26 Jennifer Yoon,¹¹ Hannah Ro,¹¹ Fatema Haidery,¹¹ Rosalie M. Grijalva,^1,2 Eunwoo Bae,¹¹ Kristen Kim,^1,12 Regina T. Martuscello,⁹ Harry T. Orr,¹³ Huda Y. Zoghbi,^14,15,16,17 Hayley S. McLoughlin,¹⁸ Laura P.W. Ranum,¹⁹ Vikram G. Shakkottai,⁷ Phyllis L. Faust,⁹ Siyuan Wang,^5,20,* David van Dijk,^3,4,* and Janghoo Lim ^{1,2,5,10,21,22,27,*}

¹Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA

²Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA

³Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA

⁴Department of Computer Science, Yale University, New Haven, CT 06510, USA

⁵Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA

⁶University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA

⁷Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

⁸Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA

⁹Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA

¹⁰Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06510, USA

¹¹Yale College, New Haven, CT 06510, USA

¹²Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA

¹³Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA

¹⁴Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA

¹⁵Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA

¹⁶Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

¹⁷Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA

¹⁸Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200, USA

¹⁹Department of Molecular Genetics and Microbiology, Center for Neurogenetics, College of Medicine, Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA

²⁰Department of Cell Biology, Yale School of Medicine, New Haven, CT 06510, USA

²¹Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA

²²Wu Tsai Institute, Yale School of Medicine, New Haven, CT 06510, USA

²³These authors contributed equally

²⁴Present address: Denali Therapeutics Inc., South San Francisco, CA 94080, USA

²⁵Present address: Artificial Intelligence Lab, Illumina Inc., Foster City, CA 94404, USA

²⁶Present address: School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China

²⁷Lead contact

*Corresponding authors: correspondence to Leon Tejwani, Siyuan Wang, David van Dijk or Janghoo Lim

Abstract

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-12-18)
연구진국외 연구진
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