Disruption of the ATXN1-CIC Complex Reveals the Role of Additional Nuclear ATXN1 Interactors in Spinocerebellar Ataxia Type 1

Authors

Stephanie L Coffin
Mark A Durham
Larissa Nitschke
Eder Xhako
Amanda M Brown
Jean-Pierre Revelli
Esmeralda Villavicencio Gonzalez
Tao Lin
Hillary P Handler
Yanwan Dai
Alexander J Trostle
Ying-Wooi Wan
Zhandong Liu
Roy V Sillitoe
Harry T Orr
Huda Y Zoghbi

Publication Date

2-15-2023

Journal

Neuron

DOI

10.1016/j.neuron.2022.11.016

PMID

36577402

PMCID

PMC9957872

PubMedCentral® Posted Date

2-25-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Mice, Animals, Ataxin-1, Spinocerebellar Ataxias, Purkinje Cells, Alleles, Mutation, Cerebellum, Regulatory Factor X1

Abstract

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.