Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

Neuron. 2023 Feb 15;111(4):481-492.e8. doi: 10.1016/j.neuron.2022.11.016. Epub 2022 Dec 27.


Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

Keywords: ATXN1; CIC; CUT&RUN; SCA1; neurodegeneration; polyglutamine expansion disorders; proteomics; regional vulnerability; spinocerebellar ataxia type 1; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Ataxin-1 / genetics
  • Cerebellum / metabolism
  • Mice
  • Mutation / genetics
  • Purkinje Cells / metabolism
  • Regulatory Factor X1 / genetics
  • Regulatory Factor X1 / metabolism
  • Spinocerebellar Ataxias* / metabolism


  • Ataxin-1
  • Atxn1 protein, mouse
  • Rfx1 protein, mouse
  • Regulatory Factor X1