Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization

ELife
Ahmed M MalikSami J Barmada

Abstract

Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3's zinc finger domains partially modulated toxicity, but elimination of its RNA recognition motifs had no effect on survival, instead facilitating its self-assembly into liquid-like droplets. In contrast to other RNA-binding proteins associated with ALS, cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. Our findings offer a foundation for understanding MATR3-related neurodegeneration and how nucleic acid binding functions, localization, and pathogenic mutations drive sporadic and familial disease.

References

Nov 1, 1987·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·E Christensen
Nov 1, 1970·Proceedings of the National Academy of Sciences of the United States of America·L Goldstein, O H Trescott
May 24, 1996·The Journal of Biological Chemistry·H InagakiY Kitagawa
Oct 11, 2002·Human Molecular Genetics·Lynne J HockingStuart H Ralston
Mar 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Montserrat Arrasate, Steven Finkbeiner
Apr 19, 2006·BMC Bioinformatics·Kang PengZoran Obradovic
Jul 4, 2006·Biochimica Et Biophysica Acta·Yasuhide HibinoKoichi Hiraga
Jan 16, 2007·Biochemical and Biophysical Research Communications·Shoji Hisada-IshiiYasuo Kitagawa
Aug 19, 2007·Nature Protocols·Dmitriy M ChudakovKonstantin A Lukyanov
Feb 21, 2008·Cell Biochemistry and Biophysics·Kathryn J BrayerDavid J Segal
Apr 25, 2008·Proceedings of the National Academy of Sciences of the United States of America·Brian S JohnsonAaron D Gitler
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sami J BarmadaSteven Finkbeiner
Apr 28, 2010·Cell Cycle·Maayan SaltonYosef Shiloh
Jul 8, 2010·The EMBO Journal·Dorothee DormannChristian Haass
Dec 15, 2010·Neuron·Janel O JohnsonBryan J Traynor
Jan 6, 2011·The Journal of Clinical Investigation·Lionel M IgazVirginia M-Y Lee
Mar 26, 2011·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·N TicozziJ E Landers
Aug 23, 2011·PloS One·Maayan SaltonYosef Shiloh
Nov 16, 2011·Archives of Neurology·Faisal FectoTeepu Siddique
Mar 13, 2012·Trends in Biochemical Sciences·Jon BurdachMerlin Crossley
Jun 28, 2013·Human Molecular Genetics·Ryoko IharaTakeshi Iwatsubo
Feb 11, 2014·The Journal of Clinical Investigation·Haiyan QiuEric J Huang
Apr 2, 2014·Nature Neuroscience·Janel O JohnsonBryan J Traynor
Jun 30, 2014·Nature Chemical Biology·Sami J BarmadaSteven Finkbeiner
Mar 17, 2015·Neurobiology of Aging·Kon-Ping LinYi-Chung Lee

❮ Previous
Next ❯

Citations

May 16, 2020·Human Molecular Genetics·Diana C CoxThomas A Cooper
Aug 20, 2020·Acta Neuropathologica Communications·Nandini RameshUdai Bhan Pandey
Nov 13, 2019·The Journal of Clinical Investigation·Kaitlin WeskampSami J Barmada
Jun 18, 2020·Frontiers in Molecular Neuroscience·Yuan Chao XueHonglin Luo
Apr 26, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·M Carolina Gallego-IradiDavid R Borchelt
Jul 19, 2020·Human Molecular Genetics·Julia E GersonLisa M Sharkey
May 30, 2019·Frontiers in Neurology·Udaya Geetha VijayakumarStephanie Marie-Rose Duguez
Oct 22, 2020·Nature Communications·Ching Serena KaoJeehye Park
Dec 31, 2020·Human Molecular Genetics·Amrutha PattamattaLaura P W Ranum
Jan 12, 2021·JCI Insight·Ahmed M Malik, Sami J Barmada
Oct 21, 2020·Neurology·Sara Saez-AtienzarBryan J Traynor
Oct 20, 2018·Experimental Eye Research·Qitao ZhangJason M L Miller
Jun 29, 2021·Biochemical and Biophysical Research Communications·Rebekah van BruggenJeehye Park
Jul 24, 2021·Neuron·Jacob R Mann, Christopher J Donnelly
Jul 26, 2021·The Journal of Biological Chemistry·Nathaniel SafrenSami J Barmada
Aug 13, 2021·Neural Regeneration Research·Caroline Ward, Udai Bhan Pandey
Sep 21, 2021·EMBO Molecular Medicine·Indranil MalikPeter K Todd
Aug 7, 2020·Cell Chemical Biology·Yan LiuKenneth D Westover

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence microscopy
Transfection
Fluorescence recovery after photobleaching
confocal microscopy
PCR
Fluorescence

Software Mentioned

μManager
R
GraphPad
Prism
ImageJ
Elements
Fiji

Related Concepts

Related Feeds

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.