ArticleProceedings of the National Academy of Sciences of the United States of America2012
CAG expansion induces nucleolar stress in polyglutamine diseases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 143 citations in OpenAlex.
- Aberrant expression of the MID1 protein in neurons of Huntington's disease brain.Frontiers in genetics · 2026Article
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- Mutant MAPT Induces rDNA Transcriptional Hyperactivation and Nucleolar Stress in Cellular Models.Research square · 2025Article
- Ivabradine induces RAD51 degradation, potentiating PARP inhibitor efficacy in non-germline BRCA pathogenic variant triple-negative breast cancer.Journal of translational medicine · 2025Article
- Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2.Acta pharmacologica Sinica · 2025Article
- Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5.Nature communications · 2025Article
- Peripheral Blood Gene Expression Profiling Reveals Molecular Pathways Associated with Cervical Artery Dissection.International journal of molecular sciences · 2024Article
- The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases.The Biochemical journal · 2024Review
- Nucleolar stress: Molecular mechanisms and related human diseases.Cancer science · 2023Review
- Nucleolar stress: From development to cancer.Seminars in cell & developmental biology · 2023Review
- G-Quadruplexes in Repeat Expansion Disorders.International journal of molecular sciences · 2023Review
- The length of uninterrupted CAG repeats in stem regions of repeat disease associated hairpins determines the amount of short CAG oligonucleotides that are toxic to cells through RNA interference.Cell death & disease · 2022Article
- Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease.International journal of molecular sciences · 2022Article
- Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington's Disease: A Pilot Study.International journal of molecular sciences · 2022Article
- Review
- A peptide inhibitor that rescues polyglutamine-induced synaptic defects and cell death through suppressing RNA and protein toxicities.Molecular therapy. Nucleic acids · 2022Article
- Molecular insights into the interaction of CAG trinucleotide RNA repeats with nucleolin and its implication in polyglutamine diseases.Nucleic acids research · 2022Article
- Nucleolar Organizer Regions as Transcription-Based Scaffolds of Nucleolar Structure and Function.Results and problems in cell differentiation · 2022Article
- Nucleolar stress controls mutant Huntington toxicity and monitors Huntington's disease progression.Cell death & disease · 2021Article
- RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2.Movement disorders : official journal of the Movement Disorder Society · 2021Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.