Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1
Year: 2023
Type: article
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.
Source: Neuron
Authors: Leon Tejwani, Neal G. Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M. Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M. Grijalva, Eunwoo Bae, Kristen Kim, Regina T. Martuscello, Harry T. Orr, Huda Y. Zoghbi, Hayley S. McLoughlin, Laura P.W. Ranum, Vikram G. Shakkottai, Phyllis L. Faust, Siyuan Wang, David van Dijk, Janghoo Lim
Institutions: Yale University, University of California, San Francisco, University of Michigan, The University of Texas Southwestern Medical Center, NewYork–Presbyterian Hospital, Columbia University Irving Medical Center, University of Minnesota, Howard Hughes Medical Institute, Baylor College of Medicine, Texas Children's Hospital, University of Florida
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,080
Funders: U.S. Department of Veterans Affairs, National Ataxia Foundation, Yale University, University of Miami, University of Michigan, China Scholarship Council, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Awards: G1051825479, Michigan Alzheimer's Disease Core Center, G2673083303, Investigating the Pathogenesis of Cerebellar Neurodegeneration, G5164331948, Integrative single-cell spatial genomic, transcriptomic, and epigenetic imaging in mammalian tissue, Identifying symptomatic and neuroprotective strategies for cereballar ataxia, Cellular and Molecular Studies of SBMA Neuromuscular Disease, Regulation of inhibitory interneuron development, G9000030919, G9000053706, G9000058985, G9000160168, G9000178431, G9000218452, G9000240352, G9000333740, Molecular Studies of Spinocerebellar Ataxia Type 1, Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases, Interdepartmental Neuroscience Program, Neurobiology of Cortical Systems, Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases
OpenAlex ID: W4389060189