Duncan NRI Faculty and Staff Publications
Publication Date
2-7-2024
Journal
Neuron
DOI
10.1016/j.neuron.2023.10.039
PMID
38016472
PMCID
PMC10922326
PubMedCentral® Posted Date
2-7-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Mice, Humans, Ataxin-1, Mice, Transgenic, Spinocerebellar Ataxias, Cerebellum, Purkinje Cells, Disease Models, Animal, spinocerebellar ataxia type 1, SCA1, ataxin-1, neurodegeneration, single-nucleus RNA sequencing, Purkinje cell, unipolar brush cells, oligodendrocyte progenitor cell, oligodendrocyte, machine learning
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.