Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

• Published in: Nature communications Vol. 14; no. 1; p. 8420
• Main Authors: Chen, Zhefan Stephen, Ou, Mingxi, Taylor, Stephanie, Dafinca, Ruxandra, Peng, Shaohong Isaac, Talbot, Kevin, Chan, Ho Yin Edwin
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.12.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; beta Catenin - genetics; beta Catenin - metabolism; Binding; C9orf72 Protein - genetics; Cell death; Chromosome 9; Dementia; Dementia disorders; DNA Repeat Expansion; Frontotemporal dementia; Frontotemporal Dementia - genetics; Fuzzy control; Humans; Kinases; Mutants; Mutation; Neurodegeneration; Neurons; Protein expression; Proteins; Ribonucleic acid; RNA; Signal transduction; Transcription; Wnt protein; YY1 protein; YY1 Transcription Factor - genetics; YY1 Transcription Factor - metabolism; Zinc finger proteins; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44215-w

The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the Fuzzy promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1-Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.