Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1)

Katherine Hamel; Emmanuel Labrada Moncada; Carrie Sheeler; Juao-Guilherme Rosa; Stephen Gilliat; Ying Zhang; Marija Cvetanovic

doi:10.1016/j.nbd.2024.106530

Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1)

Neurobiol Dis. 2024 May 14:197:106530. doi: 10.1016/j.nbd.2024.106530. Online ahead of print.

Authors

Katherine Hamel¹, Emmanuel Labrada Moncada¹, Carrie Sheeler², Juao-Guilherme Rosa³, Stephen Gilliat⁴, Ying Zhang⁵, Marija Cvetanovic⁶

Affiliations

¹ Department of Neuroscience, University of Minnesota, USA.
² Current affiliation NIH/NIDDK, USA.
³ Department of Neuroscience, University of Minnesota, USA; Current affiliation Graduate Program for Neuroscience, Boston University, 677 Beacon Street, Boston, MA 02215, USA.
⁴ Department of Neuroscience, University of Minnesota, USA; Current affiliation Department of Neuroscience, Yale University, USA.
⁵ Department of Neuroscience, University of Minnesota, USA; Minnesota Supercomputing Institute, University of Minnesota, USA; Institute for Translational Neuroscience, University of Minnesota, 2101 6(th) Street SE, Minneapolis, MN 55455, USA.
⁶ Department of Neuroscience, University of Minnesota, USA; Institute for Translational Neuroscience, University of Minnesota, 2101 6(th) Street SE, Minneapolis, MN 55455, USA. Electronic address: mcvetano@umn.edu.

PMID: 38750673
DOI: 10.1016/j.nbd.2024.106530

Abstract

Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice.

Keywords: Cerebellum; Heterogeneity; Neurodegeneration; SCA1; Selective vulnerability.