G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD.

Neuron
Alyssa N CoyneJeffrey D Rothstein

Abstract

Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.

References

Jun 20, 2001·Current Biology : CB·F Melchior
Feb 12, 2008·Nucleic Acids Research·Robert J Osborne, Charles A Thornton
Jun 17, 2010·Cell·Christine M DoucetMartin W Hetzer
Jan 13, 2011·Current Alzheimer Research·R FerrariP Momeni
Jul 6, 2011·The Journal of Cell Biology·Jessica A Talamas, Martin W Hetzer
Feb 4, 2012·Science·Jeffrey N SavasMartin W Hetzer
Oct 24, 2012·Nature Reviews. Molecular Cell Biology·Marcela Raices, Maximiliano A D'Angelo
Jun 27, 2013·Nature Neuroscience·Marta Maglione, Stephan J Sigrist
Aug 13, 2013·Neuron·Shuo-Chien LingDon W Cleveland
Oct 22, 2013·Neuron·Christopher J DonnellyJeffrey D Rothstein
Oct 25, 2013·Science Translational Medicine·Dhruv SareenRobert H Baloh
Oct 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Clotilde Lagier-TourenneJohn Ravits
May 27, 2014·Methods in Cell Biology·Boris FichtmanAmnon Harel
Jan 30, 2015·Molecular Biology of the Cell·Petra PopkenLiesbeth M Veenhoff
Aug 27, 2015·Nature·Ke ZhangJeffrey D Rothstein
Aug 27, 2015·Nature·Brian D FreibaumJ Paul Taylor
Mar 22, 2016·Nature Neuroscience·Yong-Jie ZhangLeonard Petrucelli
Mar 30, 2016·Nature Neuroscience·Samuel SancesClive N Svendsen
Apr 10, 2016·Brain Research·Aaron D Gitler, Hitomi Tsuiji
Oct 19, 2016·Nucleus·Christina LiWeidong Yang
Oct 5, 2016·The Journal of Cell Biology·Benjamin L TimneyMichael P Rout
Nov 1, 2016·Brain : a Journal of Neurology·Sarat C VatsavayaiWilliam W Seeley
Nov 11, 2016·Nature·J Paul TaylorDon W Cleveland
Dec 22, 2016·Nature Reviews. Molecular Cell Biology·Martin Beck, Ed Hurt
Jan 11, 2017·Proceedings of the National Academy of Sciences of the United States of America·Kevin Y ShiSteven L McKnight
Mar 31, 2017·Science Translational Medicine·Tania F GendronLeonard Petrucelli
Apr 7, 2017·Neuron·Jonathan C GrimaJeffrey D Rothstein
May 17, 2017·Acta Neuropathologica·Mariely DeJesus-HernandezRosa Rademakers
Jan 10, 2018·Nature Neuroscience·Ching-Chieh ChouWilfried Rossoll

❮ Previous
Next ❯

Citations

Oct 7, 2020·Neuron·Daniel A MordesJeffrey D Rothstein
Feb 11, 2021·Trends in Biochemical Sciences·Javier Fernandez-Martinez, Michael P Rout
Mar 21, 2021·Acta Neuropathologica Communications·Alyssa N Coyne, Jeffrey D Rothstein
Apr 2, 2021·The EMBO Journal·Maria Elena CicardiDavide Trotti
May 1, 2021·International Journal of Molecular Sciences·Baojin Ding, Masood Sepehrimanesh
May 11, 2021·Frontiers in Cellular Neuroscience·Daniel A SolomonSarah Mizielinska
Aug 6, 2021·Frontiers in Cellular Neuroscience·Benjamin L Zaepfel, Jeffrey D Rothstein
Jul 21, 2021·Acta Neuropathologica Communications·Alyssa N Coyne, Jeffrey D Rothstein
Sep 2, 2021·Annual Review of Biomedical Data Science·Jonathan Li, Ernest Fraenkel
Oct 30, 2021·The Journal of Cell Biology·Sunandini ChandraC Patrick Lusk
Oct 23, 2021·Journal of Neurochemistry·Paulina TorresClaudio Hetz

❮ Previous
Next ❯

Related Concepts

Related Feeds

Researcher Network:CZI Neurodegeneration Challenge

The Neurodegeneration Challenge Network aims to provide funding for and to bring together researchers studying neurodegenerative diseases. Find the latest research from the NDCN grantees here.

Antisense Oligonucleotides: ND

This feed focuses on antisense oligonucleotide therapies such as Inotersen, Nusinursen, and Patisiran, in neurodegenerative diseases including amyotrophic lateral sclerosis.

Brain developing: Influences & Outcomes

This feed focuses on influences that affect the developing brain including genetics, fetal development, prenatal care, and gene-environment interactions. Here is the latest research in this field.

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.