Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation

Human Molecular Genetics
Yoshinori TanakaMasato Hasegawa

Abstract

Profilin 1 (PFN1) is an actin monomer-binding protein essential for regulating cytoskeletal dynamics in all cell types. Recently, mutations in the PFN1 gene have been identified as a cause of familial amyotrophic lateral sclerosis (ALS). The co-aggregation of PFN1 bearing mutations that cause ALS with TDP-43 (a key molecule in both sporadic and some familial forms of ALS), together with the classical TDP-43 pathology detected in post-mortem tissues of patients with autosomal dominant PFN1 mutation, imply that gain-of-toxic-function of PFN1 mutants is associated with the onset of ALS. However, it remains unknown how PFN1 mutants cause ALS. We found mutant PFN1 that causes ALS formed cytoplasmic aggregates positive for ubiquitin and p62, and these aggregates sequestered endogenous TDP-43. In cells harboring PFN1 aggregates, formation of aggresome-like structures was inhibited in the presence of proteasome inhibitor, and conversion of LC3-I to LC3-II was suppressed in the presence of lysosome inhibitor. Further, insoluble TDP-43 was increased in both cases. Co-expression of ALS-linked mutant PFN1 and TDP-43 increased insoluble and phosphorylated TDP-43 levels. The C-terminal region of TDP-43, essential for aggregation of TDP-43, w...Continue Reading

References

Mar 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·W WitkeD J Kwiatkowski
Mar 1, 2008·Science·Jemeen SreedharanChristopher E Shaw
Jun 12, 2008·Annals of Neurology·Masato HasegawaHaruhiko Akiyama
Jul 29, 2008·FEBS Letters·Yuki InukaiMasato Hasegawa
Sep 20, 2008·PLoS Genetics·Nicola J RutherfordRosa Rademakers
Jun 12, 2009·Human Molecular Genetics·Takashi NonakaMasato Hasegawa
Jul 28, 2009·Biochemistry·Takashi Nonaka, Masato Hasegawa
Jan 28, 2010·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Tetsuaki AraiHaruhiko Akiyama
Jul 20, 2010·RNA Biology·Emanuele Buratti, Francisco Ernesto Baralle
Jun 17, 2011·Journal of Molecular Neuroscience : MN·Masato HasegawaHaruhiko Akiyama
Dec 1, 2011·Nature Reviews. Neuroscience·Edward B LeeJohn Q Trojanowski
Oct 16, 2012·Neurobiology of Aging·Cinzia TilocaUNKNOWN SLAGEN Consortium
Dec 21, 2012·EMBO Molecular Medicine·Hitomi TsuijiKoji Yamanaka
May 3, 2013·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Marka van BlitterswijkRosa Rademakers
Jun 7, 2013·Human Molecular Genetics·Tomohiko IshiharaOsamu Onodera
Jul 9, 2013·Cell Reports·Takashi NonakaMasato Hasegawa
Dec 7, 2013·Journal of Neurology, Neurosurgery, and Psychiatry·Pietro FrattaElizabeth M C Fisher
Apr 5, 2014·Human Molecular Genetics·Makiko YamashitaMasato Hasegawa
Jun 13, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Matthew D FigleyAaron D Gitler
Aug 19, 2014·Frontiers in Molecular Neuroscience·Nico P Dantuma, Laura C Bott
Dec 17, 2014·Neurobiology of Aging·Bradley N SmithChristopher E Shaw
Apr 22, 2015·Molecules and Cells·Jihoon NahYong-Keun Jung
Jun 10, 2015·Proceedings of the National Academy of Sciences of the United States of America·Sivakumar BoopathyDaryl A Bosco

❮ Previous
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Citations

Mar 8, 2013·PloS One·Lihong ZhanRandal S Tibbetts
Nov 17, 2012·PloS One·Marka van BlitterswijkLeonard H van den Berg
Jul 20, 2016·Prion·Yoshinori Tanaka, Masato Hasegawa
Nov 26, 2013·European Journal of Cell Biology·Bo Xue, Robert C Robinson
Sep 28, 2016·Cellular and Molecular Life Sciences : CMLS·Duah AlkamMahmoud Kiaei
Aug 9, 2016·American Journal of Human Genetics·Seyyedmohsen HosseinibarkooieBrunhilde Wirth
Jan 12, 2017·Human Molecular Genetics·Yoshinori TanakaMasugi Nishihara
Jan 4, 2017·Human Molecular Genetics·Daniel FilMahmoud Kiaei
Feb 12, 2019·Critical Reviews in Biochemistry and Molecular Biology·S ParakhJ D Atkin
May 26, 2017·Frontiers in Molecular Neuroscience·Hamideh ShahheydariJulie D Atkin
Mar 19, 2020·Brain : a Journal of Neurology·Carol Dobson-StoneJohn B Kwok
Nov 14, 2016·Cellular and Molecular Life Sciences : CMLS·Nikolas SantamariaVladimir N Uversky
Sep 28, 2017·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Takashi NonakaMasato Hasegawa
Mar 7, 2019·Frontiers in Molecular Neuroscience·Archana PrasadBasant K Patel
May 18, 2020·Journal of Molecular Neuroscience : MN·E Srinivasan, R Rajasekaran
Sep 12, 2018·Metabolic Brain Disease·Mina NekoueiAlireza Ghassempour
May 15, 2019·Biology·Veronica Granatiero, Giovanni Manfredi
Apr 6, 2017·Human Molecular Genetics·Chi-Hong WuJohn E Landers
May 4, 2017·Molecular Neurobiology·Moritz OberstadtMax Holzer
Jan 28, 2021·International Journal of Molecular Sciences·Elżbieta PaszekPaweł Kleczyński
Dec 22, 2019·Current Opinion in Neurobiology·Takashi Nonaka, Masato Hasegawa
Apr 8, 2018·Neuroscience Letters·Dao K H NguyenJiou Wang
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Kai MurkJuliane Schiweck

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