Abnormal RNA stability in amyotrophic lateral sclerosis

Nature Communications
E M TankS J Barmada

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA-binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in postmortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.

References

Dec 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Benjamin P LewisSteven E Brenner
Apr 12, 2003·Neurology·C Lomen-HoerthB Miller
Apr 13, 2007·American Journal of Physiology. Cell Physiology·Werner J H KoopmanPeter H G M Willems
Apr 25, 2008·Proceedings of the National Academy of Sciences of the United States of America·Brian S JohnsonAaron D Gitler
Aug 30, 2008·Human Molecular Genetics·Iris EisenbergStella Mitrani-Rosenbaum
Dec 11, 2008·Annals of Neurology·Heather MortiboysOliver Bandmann
Mar 24, 2009·Nature Methods·Enrico K SchmidtPhilippe Pierre
Sep 22, 2009·Journal of Neurochemistry·Claudia ColombritaAntonia Ratti
Dec 31, 2009·The Journal of Biological Chemistry·Chantelle F SephtonGang Yu
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sami J BarmadaSteven Finkbeiner
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hans WilsSamir Kumar-Singh
Mar 18, 2010·Current Protocols in Cell Biology·Kasturi Mitra, Jennifer Lippincott-Schwartz
Nov 6, 2010·The Journal of Biological Chemistry·Chantelle F SephtonGang Yu
Jan 25, 2011·Human Molecular Genetics·Karli K McDonaldChristine Vande Velde
Mar 2, 2011·Nature Neuroscience·James R TollerveyJernej Ule
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Mar 11, 2011·PloS One·Junying YuYong Jiang
Aug 30, 2011·Free Radical Biology & Medicine·Brian P DrankaVictor M Darley-Usmar
Jan 19, 2012·Brain : a Journal of Neurology·Azusa UchidaTakanori Yokota
Apr 6, 2012·PLoS Genetics·Alex M Plocik, Christine Guthrie
Apr 14, 2012·Nature Reviews. Neuroscience·Hosung JungChristine E Holt
Jun 27, 2012·Nature Reviews. Neurology·Rosa RademakersIan R Mackenzie
Aug 21, 2012·Acta Neuropathologica·Ammar Al-ChalabiLeonard H van den Berg
Nov 30, 2012·Nucleic Acids Research·Tanya BarrettAlexandra Soboleva
Jan 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·Michelle T PaulsenMats Ljungman
Feb 6, 2013·Clinical Genetics·M SabatelliM Zollino
Oct 22, 2013·Neuron·Christopher J DonnellyJeffrey D Rothstein
Feb 11, 2014·The Journal of Clinical Investigation·Haiyan QiuEric J Huang
Jun 21, 2014·Seminars in Cell & Developmental Biology·Pauline Adjibade, Rachid Mazroui
Jun 30, 2014·Nature Chemical Biology·Sami J BarmadaSteven Finkbeiner
Nov 5, 2014·Nature Reviews. Genetics·Stefanie GerstbergerThomas Tuschl
Feb 19, 2015·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Sami J Barmada
Apr 8, 2015·The Journal of Cell Biology·Anaïs AulasChristine Vande Velde
Jun 10, 2015·Proceedings of the National Academy of Sciences of the United States of America·Sami J BarmadaSteven Finkbeiner
Aug 8, 2015·Science·Jonathan P LingPhilip C Wong
Aug 27, 2015·Nature·Ke ZhangJeffrey D Rothstein
Aug 27, 2015·Nature·Brian D FreibaumJ Paul Taylor

❮ Previous
Next ❯

Citations

Dec 18, 2018·Transcription·Emma R HinkleJimena Giudice
Dec 24, 2018·Neuropathology and Applied Neurobiology·B BorroniE Buratti
Dec 7, 2018·FEBS Letters·Makoto FukushimaShin-Ichi Hoshino
Jun 28, 2019·Frontiers in Neuroscience·Thomas J HedlAlbert Lee
Jun 6, 2019·Frontiers in Neurology·Jisen Huai, Zhongjian Zhang
Jul 19, 2019·Frontiers in Neuroscience·Audrey M G RagagninJulie D Atkin
Sep 25, 2020·International Journal of Molecular Sciences·Banaja P DashAndreas Hermann
May 7, 2020·Frontiers in Neuroscience·Lin Wang, Lijuan Zhang
May 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Josiah J HerzogSuzanne Paradis
Jan 31, 2020·Frontiers in Molecular Biosciences·Suvithanandhini LoganathanDaniela C Zarnescu
Jul 29, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ranjit K MehtaMukesh K Nyati
Mar 26, 2021·Acta Neuropathologica Communications·Erik M LehmkuhlDaniela C Zarnescu
Mar 23, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Xinwen ZhangXin Qi
Mar 15, 2019·Journal of the Neurological Sciences·Stéphane MathisGwendal Le Masson
Jan 2, 2021·Trends in Molecular Medicine·Kaitlin WeskampRoy Parker
May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea
Jul 3, 2021·International Journal of Molecular Sciences·Elena ObradorJosé M Estrela
Jul 2, 2021·Frontiers in Molecular Neuroscience·Seiichi Nagano, Toshiyuki Araki
Aug 6, 2021·Frontiers in Cellular Neuroscience·Benjamin L Zaepfel, Jeffrey D Rothstein
Mar 31, 2021·Journal of Molecular Cell Biology·Paul Jongseo LeeJunjie U Guo
Sep 2, 2021·Annual Review of Biomedical Data Science·Jonathan Li, Ernest Fraenkel
Jun 12, 2021·Brain : a Journal of Neurology·Hadjara SidibéChristine Vande Velde
Dec 3, 2021·Journal of Cell Science·Imadeddin HijaziAmy Chang

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE115310
PXD009969

Methods Mentioned

BETA
immunoprecipitation
RNA-seq
PCR
transfection
transfections
Illumina sequencing
deamidation
Flow Cytometry
fluorescence microscopy

Software Mentioned

R
Pluritest
Bowtie
NIS
DESeq
STRING
TopHat
Search Tool for the
SUnSET
Proteome Discoverer

Related Concepts

Related Feeds

ALS: Genetics

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating genetic alterations in this genetically heterogeneous disorder.

ALS: Genetics

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. ALS is a genetically heterogeneous disorder with several causative genes. Here are the latest discoveries pertaining to the genetics of this disease.

ALS & FTD: TDP-43

TAR DNA-binding protein 43 (TDP-43) is a pathological protein identified in sporadic Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Here are the latest discoveries pertaining to TDP-43 and these diseases.

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.