Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.

TitleNeurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.
Publication TypeJournal Article
Year of Publication2016
AuteursYadav, P, Selvaraj, BT, Bender, FLP, Behringer, M, Moradi, M, Sivadasan, R, Dombert, B, Blum, R, Asan, E, Sauer, M, Julien, J-P, Sendtner, M
JournalActa Neuropathol
Volume132
Issue1
Pagination93-110
Date Published2016 Jul
ISSN1432-0533
KeywordsAnimals, Axons, Cells, Cultured, Kaplan-Meier Estimate, Mice, Inbred C57BL, Mice, Transgenic, Molecular Chaperones, Motor Activity, Motor Neurons, Neurofilament Proteins, Phenotype, Phrenic Nerve, Sciatic Nerve, Signal Transduction, Spinal Cord, STAT3 Transcription Factor, Stathmin
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.

DOI10.1007/s00401-016-1564-y
Alternate JournalActa Neuropathol.
PubMed ID27021905
PubMed Central IDPMC4911381