Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1

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. ZoghbiHayley S. McLoughlin, Laura P.W. Ranum, Vikram G. Shakkottai, Phyllis L. Faust, Siyuan Wang, David van Dijk, Janghoo Lim

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)362-383.e15
JournalNeuron
Volume112
Issue number3
DOIs
StatePublished - Feb 7 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

  • Purkinje cell
  • SCA1
  • ataxin-1
  • machine learning
  • neurodegeneration
  • oligodendrocyte
  • oligodendrocyte progenitor cell
  • single-nucleus RNA sequencing
  • spinocerebellar ataxia type 1
  • unipolar brush cells

PubMed: MeSH publication types

  • Journal Article

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