Co-expression of truncated and full-length tau induces severe neurotoxicity

Molecular Psychiatry
Sefika OzcelikDavid T Winkler

Abstract

Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular-weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in the presence of full-length tau through the formation of nonfilamentous high-molecular-weight tau aggregates, in the absence of tau filaments. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies.

References

Jun 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·C M WischikA Klug
May 11, 2000·Acta Neuropathologica·A ProbstM Goedert
Jul 12, 2002·Annals of Neurology·David T WinklerMathias Jucker
Dec 31, 2002·Neurobiology of Disease·Troy T RohnElizabeth Head
Apr 23, 2003·The American Journal of Pathology·Adam D CashGeorge Perry
Jul 31, 2003·Proceedings of the National Academy of Sciences of the United States of America·T Chris GamblinVincent L Cryns
Sep 10, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Peleg M HorowitzLester I Binder
Apr 28, 2005·The American Journal of Pathology·Dalinda LiazoghliNicole Leclerc
Jan 13, 2006·Neuroscience Research·Sumihiro MaedaAkihiko Takashima
May 3, 2006·The American Journal of Pathology·Tara L SpiresBradley T Hyman
Apr 6, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zdenek BergerChristopher Janus
May 31, 2007·Proceedings of the National Academy of Sciences of the United States of America·Y P WangE-M Mandelkow
Dec 15, 2007·The American Journal of Pathology·Patrice DelobelMichel Goedert
Jun 9, 2009·Nature Cell Biology·Florence ClavagueraMarkus Tolnay
Jun 12, 2009·Human Molecular Genetics·Takashi NonakaMasato Hasegawa
Oct 16, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gerardo A MorfiniScott T Brady
Apr 2, 2010·Nature·Alix de CalignonBradley T Hyman
Jul 29, 2010·PLoS Genetics·Vikram KhuranaMel B Feany
Sep 11, 2010·Science·Keith A VosselLennart Mucke
Nov 5, 2010·Nature Reviews. Neurology·Jesús Avila
Dec 4, 2010·Human Molecular Genetics·Alexis R DemonbreunElizabeth M McNally
Jan 5, 2011·Neurobiology of Aging·Peter FilipcikMichal Novak
May 10, 2011·The Journal of Biological Chemistry·Kristina R PattersonLester I Binder
Jun 4, 2011·Journal of Molecular Neuroscience : MN·Tara L Spires-JonesBradley T Hyman
Aug 26, 2011·Journal of Neuropathology and Experimental Neurology·Wen-Lang LinNaruhiko Sahara
Dec 14, 2011·The Journal of Clinical Investigation·Cao HuangXu-Gang Xia
Jan 19, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cristian A Lasagna-ReevesRakez Kayed
Mar 20, 2012·Cell·David Eisenberg, Mathias Jucker
Jun 8, 2012·Cold Spring Harbor Perspectives in Medicine·Colin L Masters, Dennis J Selkoe
Oct 11, 2012·Scientific Reports·Cristian A Lasagna-ReevesRakez Kayed
Nov 28, 2012·Nature Reviews. Neurology·Michel GoedertHeiko Braak
Mar 19, 2013·Molecular Cell·Christopher S BrowerAlexander Varshavsky
May 21, 2013·Lancet Neurology·Maria Grazia Spillantini, Michel Goedert
Jul 25, 2013·Frontiers in Neurology·Julia E Gerson, Rakez Kayed
Sep 4, 2013·The Journal of Clinical Investigation·Laura J BlairChad A Dickey
Nov 23, 2013·Nature Protocols·Marianne LegerThomas Freret
Dec 24, 2013·Acta Neuropathologica·Florence ClavagueraMarkus Tolnay
Jan 28, 2014·Nature Neuroscience·Bess FrostMel B Feany

❮ Previous
Next ❯

Citations

Jan 14, 2017·Molecular Neurobiology·María José PérezRodrigo A Quintanilla
Jan 25, 2017·Neuropathology and Applied Neurobiology·P Andrés-BenitoI Ferrer
Jul 19, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Pei-Pei Guan, Pu Wang
Aug 5, 2017·Annual Review of Neuroscience·Michel GoedertR Anthony Crowther
Oct 19, 2016·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Michel Goedert
Aug 10, 2019·Brain Pathology·Isidro FerrerJosé Antonio Del Rio
Nov 24, 2016·Frontiers in Aging Neuroscience·Jesus AvilaFelix Hernández
May 9, 2019·Acta Neuropathologica Communications·Zhiva SkachokovaDavid T Winkler
Nov 3, 2016·Cold Spring Harbor Perspectives in Biology·Heiko Braak, Kelly Del Tredici
Dec 21, 2017·Acta Neuropathologica Communications·Amrit MudherJean-Pierre Brion
Apr 10, 2018·Journal of Alzheimer's Disease : JAD·James P QuinnNigel M Hooper
Jun 6, 2018·Journal of Alzheimer's Disease : JAD·Petr NovakMichal Novak
Jun 30, 2019·Alzheimer's Research & Therapy·Leslie A Sandusky-BeltranDaniel C Lee
Sep 9, 2018·Nature Reviews. Neuroscience·Jürgen GötzMichel Goedert
Jan 24, 2021·Brain : a Journal of Neurology·Alfonso MartinisiDavid T Winkler
Mar 7, 2021·Biomedicines·Liqing SongAnne Skaja Robinson
May 3, 2021·Acta Neuropathologica·Vega García-EscuderoJesús Ávila
Apr 8, 2021·Chembiochem : a European Journal of Chemical Biology·Parvathy JayanVinesh Vijayan
Jul 3, 2021·International Journal of Molecular Sciences·Aiko RobertThomas Vogels

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic

Software Mentioned

GraphPad
Graphpad Prism
ImageJ

Related Concepts

Related Feeds

Alzheimer's Disease: Tau & TDP-43

Alzheimer's disease is a neurodegenerative disease. This feed focuses on the underlying role of tau proteins and TAR DNA-binding protein 43, as well as other genetic factors, in Alzheimer's disease.