CAG expansion induces nucleolar stress in polyglutamine diseases

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-08, Vol.109 (33), p.13428-13433
• Main Authors: Tsoi, Ho, Lau, Terrence Chi-Kong, Tsang, Suk-Ying, Lau, Kwok-Fai, Chan, Ho Yin Edwin
• Format: Article
• Language: English
• Subjects: animal disease models; Animals; Apoptosis; Binding sites; Biological Sciences; caspases; Caspases - metabolism; cell nucleolus; Cell Nucleolus - genetics; cytochrome c; Cytochromes c - metabolism; Disease models; DNA; DNA methylation; DNA Methylation - genetics; Enzyme Activation; gene expression regulation; Genetic disorders; Humans; Methylation; Mice; Mitochondria; Mitochondria - genetics; Models, Biological; mutants; Nervous system diseases; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurons; Nucleolin; patients; Peptides - metabolism; Phosphoproteins - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Ribosomal proteins; ribosomal RNA; RNA; RNA Polymerase I - metabolism; RNA Stability - genetics; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; RNA-Binding Proteins - metabolism; RNA-protein interactions; Stress, Physiological - genetics; toxicity; Transcription, Genetic; Transgenic animals; Trinucleotide Repeat Expansion - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1204089109

The cell nucleus is a major site for polyglutamine (polyQ) toxicity, but the underlying mechanisms involved have yet been fully elucidated. Here, we report that mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs) induce apoptosis by activating the nucleolar stress pathway in both polyQ patients and transgenic animal disease models. We showed that expanded CAG RNAs interacted directly with nucleolin (NCL), a protein that regulates rRNA transcription. Such RNA–protein interaction deprived NCL of binding to upstream control element (UCE) of the rRNA promoter , which resulted in UCE DNA hypermethylation and subsequently perturbation of rRNA transcription. The down-regulation of rRNA transcription induced nucleolar stress and provoked apoptosis by promoting physical interaction between ribosomal proteins and MDM2. Consequently, p53 protein was found to be stabilized in cells and became concentrated in the mitochondria. Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation. Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus.