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RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin‐2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis. OBJECTIVE: Here, we tested the hypothesis t...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884117/ https://www.ncbi.nlm.nih.gov/pubmed/34390268 http://dx.doi.org/10.1002/mds.28729 |
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author | Li, Pan P. Moulick, Roumita Feng, Hongxuan Sun, Xin Arbez, Nicolas Jin, Jing Marque, Leonard O. Hedglen, Erin Chan, H.Y. Edwin Ross, Christopher A. Pulst, Stefan M. Margolis, Russell L. Woodson, Sarah Rudnicki, Dobrila D. |
author_facet | Li, Pan P. Moulick, Roumita Feng, Hongxuan Sun, Xin Arbez, Nicolas Jin, Jing Marque, Leonard O. Hedglen, Erin Chan, H.Y. Edwin Ross, Christopher A. Pulst, Stefan M. Margolis, Russell L. Woodson, Sarah Rudnicki, Dobrila D. |
author_sort | Li, Pan P. |
collection | PubMed |
description | BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin‐2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis. OBJECTIVE: Here, we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis. METHODS: The toxic effect of expATXN2 transcripts on SK‐N‐MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if ribosomal RNA (rRNA) processing is disrupted in SCA2 and Huntington's disease (HD) human brain tissue. RESULTS: expATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin β‐like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue. CONCLUSION: These findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role of expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society |
format | Online Article Text |
id | pubmed-8884117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88841172022-03-04 RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2 Li, Pan P. Moulick, Roumita Feng, Hongxuan Sun, Xin Arbez, Nicolas Jin, Jing Marque, Leonard O. Hedglen, Erin Chan, H.Y. Edwin Ross, Christopher A. Pulst, Stefan M. Margolis, Russell L. Woodson, Sarah Rudnicki, Dobrila D. Mov Disord Regular Issue Articles BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin‐2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis. OBJECTIVE: Here, we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis. METHODS: The toxic effect of expATXN2 transcripts on SK‐N‐MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if ribosomal RNA (rRNA) processing is disrupted in SCA2 and Huntington's disease (HD) human brain tissue. RESULTS: expATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin β‐like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue. CONCLUSION: These findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role of expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society John Wiley & Sons, Inc. 2021-08-14 2021-11 /pmc/articles/PMC8884117/ /pubmed/34390268 http://dx.doi.org/10.1002/mds.28729 Text en © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Regular Issue Articles Li, Pan P. Moulick, Roumita Feng, Hongxuan Sun, Xin Arbez, Nicolas Jin, Jing Marque, Leonard O. Hedglen, Erin Chan, H.Y. Edwin Ross, Christopher A. Pulst, Stefan M. Margolis, Russell L. Woodson, Sarah Rudnicki, Dobrila D. RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2 |
title |
RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
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title_full |
RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
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title_fullStr |
RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
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title_full_unstemmed |
RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
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title_short |
RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2
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title_sort | rna toxicity and perturbation of rrna processing in spinocerebellar ataxia type 2 |
topic | Regular Issue Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884117/ https://www.ncbi.nlm.nih.gov/pubmed/34390268 http://dx.doi.org/10.1002/mds.28729 |
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