Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

Journal of Cell Science
Simona RossiMauro Cozzolino

Abstract

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and...Continue Reading

References

Dec 21, 2000·The Journal of Cell Biology·N KedershaP Anderson
Feb 3, 2009·Cell Cycle·Martyn K WhiteKamel Khalili
Mar 24, 2009·Nature Methods·Enrico K SchmidtPhilippe Pierre
Sep 24, 2009·Nature Reviews. Molecular Cell Biology·Mo Chen, James L Manley
Jan 28, 2010·The Biochemical Journal·Richard W P Smith, Nicola K Gray
Feb 24, 2010·Nature Reviews. Genetics·Albert R La Spada, J Paul Taylor
Oct 23, 2010·Molecular Cell·Keith A SpriggsAnne E Willis
Apr 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·Zihui XuPeng Jin
Oct 12, 2013·American Journal of Medical Genetics. Part a·Claudia Bagni, Ben A Oostra
Oct 22, 2013·Neuron·Christopher J DonnellyJeffrey D Rothstein
Nov 22, 2013·Biochemical Society Transactions·Tilmann AchselMaria Teresa Carrì
May 29, 2014·Brain : a Journal of Neurology·Johnathan Cooper-KnockPamela J Shaw
Aug 12, 2014·Biochemical Society Transactions·Richard W P SmithNicola K Gray

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Citations

Jan 17, 2016·Nucleic Acids Research·Agnieszka M GromadzkaNiels H Gehring
Jan 19, 2016·Brain Pathology·Simona RossiMaria Teresa Carrì
Apr 27, 2016·Current Neurology and Neuroscience Reports·Martine TherrienGuy A Rouleau
May 29, 2016·Progress in Neurobiology·Mónica ZufiríaAdolfo López de Munain
Mar 27, 2016·Journal of Neurochemistry·Tiffany W Todd, Leonard Petrucelli
Aug 9, 2016·Brain : a Journal of Neurology·Sonja Prpar MihevcBoris Rogelj
Nov 2, 2016·Nucleic Acids Research·Magdalena JazurekWlodzimierz J Krzyzosiak
Feb 17, 2017·Biochemistry·Mia K MihailovicLydia M Contreras
Apr 6, 2017·FEBS Letters·Helena Ederle, Dorothee Dormann
Jan 29, 2017·Cold Spring Harbor Perspectives in Medicine·Tania F Gendron, Leonard Petrucelli
Jan 13, 2018·Frontiers in Neuroscience·Vijay KumarMd Imtaiyaz Hassan
Feb 13, 2019·Journal of Cell Science·Ana Bajc ČesnikBoris Rogelj
Apr 20, 2017·Acta Neuropathologica Communications·Sarah MizielinskaAdrian M Isaacs
Oct 4, 2017·Human Molecular Genetics·Michael TibshiraniHeather D Durham
Nov 14, 2019·The EMBO Journal·Bart SwinnenLudo Van Den Bosch
May 1, 2019·Acta Neuropathologica Communications·Amit BersonNancy M Bonini
Jul 27, 2017·Frontiers in Cellular Neuroscience·Holly V BarkerJean-Marc Gallo
Mar 28, 2018·Brain : a Journal of Neurology·Callum Walker, Sherif F El-Khamisy
Apr 16, 2019·FEBS Open Bio·Alejandra M MartinezWan Seok Yang
Feb 27, 2016·Acta Neuropathologica Communications·Michael NiblockJean-Marc Gallo
Sep 2, 2017·Frontiers in Cellular Neuroscience·Alyssa N CoyneDaniela C Zarnescu
Feb 6, 2020·Frontiers in Molecular Biosciences·Maximilian Paul Thelen, Min Jeong Kye
Mar 5, 2016·Human Molecular Genetics·Kohsuke KanekuraFumihiko Urano
May 20, 2017·Frontiers in Cellular Neuroscience·Yu-Ju LiuYijuang Chern
Aug 19, 2018·Nature Reviews. Neurology·Rubika Balendra, Adrian M Isaacs
Feb 19, 2019·Behavioural Neurology·Mirjana Babić LekoGoran Šimić
Mar 1, 2017·Frontiers in Molecular Neuroscience·Brian D Freibaum, J Paul Taylor
Apr 27, 2017·Frontiers in Cellular Neuroscience·Adam CiesiolkaWlodzimierz J Krzyzosiak
Apr 8, 2017·Frontiers in Molecular Neuroscience·Gianluca CestraMauro Cozzolino
Aug 5, 2020·Acta Neuropathologica·Alexander BamptonAriana Gatt
May 17, 2017·Acta Neuropathologica·Mariely DeJesus-HernandezRosa Rademakers
Feb 21, 2018·Brain Research·Bilal KhalilWilfried Rossoll

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