Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2023-02, Vol.111 (4), p.481-492.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. [Display omitted] •ATXN1-CIC complex drives SCA1 Purkinje cell loss but minimally affects other cells•CIC DNA binding is enhanced in SCA1 and normalized by disrupting the ATXN1-CIC complex•ATXN1 interacts with additional transcription factors RFX1, ZBTB5, and ZKSCAN1•Targets of multiple ATXN1 interactors are altered in SCA1 mice and patient cells Coffin et al. show that global ablation of the ATXN1-CIC interaction normalizes aberrant SCA1 CIC genome-wide binding in mice; however, it does not correct all transcriptional or behavioral changes. They discovered that ATXN1 interacts with multiple factors to drive SCA1, revealing the mechanistic complexity that underlies regional vulnerability in neurodegenerative diseases.