title: Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.
abstract: In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Preeti
authors.initials: P
authors.lastname: Yadav
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Bhuvaneish T
authors.initials: BT
authors.lastname: Selvaraj
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Florian L P
authors.initials: FL
authors.lastname: Bender
authors.affiliation: Department of Biotechnology and Biophysics, University of Wuerzburg, 97074, Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Behringer
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Mehri
authors.initials: M
authors.lastname: Moradi
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Rajeeve
authors.initials: R
authors.lastname: Sivadasan
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dombert
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Blum
authors.affiliation: Institute of Anatomy and Cell Biology, University of Wuerzburg, 97070, Würzburg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Asan
authors.affiliation: Department of Biotechnology and Biophysics, University of Wuerzburg, 97074, Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Department of Psychiatry and Neurosciences, Research Centre of Institut Universitaire en Santé Mentale de Québec, University Laval, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Institute of Clinical Neurobiology, University of Wuerzburg, 97078, Würzburg, Germany. Sendtner_M@ukw.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D053208:Kaplan-Meier Estimate; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D010791:Phrenic Nerve / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D050777:Stathmin / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D016900:Neurofilament Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050777:Stathmin; C493994:Stmn1 protein, mouse; C469269:Tbce protein, mouse; C044882:neurofilament protein L
keywords: Axon degeneration; Microtubules; Neurofilament; Stat3; Stathmin