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Neurofilament Depletion Improves Microtubule Dynamics Via Modulation of Stat3/Stathmin Signaling

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Neurofilament Depletion Improves Microtubule Dynamics Via Modulation of Stat3/Stathmin Signaling Edinburgh Research Explorer Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling Citation for published version: Yadav, P, Selvaraj, BT, Bender, FLP, Behringer, M, Moradi, M, Sivadasan, R, Dombert, B, Blum, R, Asan, E, Sauer, M, Julien, JP & Sendtner, M 2016, 'Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling', Acta Neuropathologica, vol. 132, no. 1, pp. 93-110. https://doi.org/10.1007/s00401-016-1564-y Digital Object Identifier (DOI): 10.1007/s00401-016-1564-y Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Acta Neuropathologica Publisher Rights Statement: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 09. Oct. 2021 Acta Neuropathol (2016) 132:93–110 DOI 10.1007/s00401-016-1564-y ORIGINAL PAPER Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling Preeti Yadav1 · Bhuvaneish T. Selvaraj1,5 · Florian L. P. Bender1 · Marcus Behringer4 · Mehri Moradi1 · Rajeeve Sivadasan1 · Benjamin Dombert1 · Robert Blum1 · Esther Asan2 · Markus Sauer4 · Jean‑Pierre Julien3 · Michael Sendtner1 Received: 24 August 2015 / Revised: 14 March 2016 / Accepted: 15 March 2016 / Published online: 28 March 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com Abstract In neurons, microtubules form a dense array motoneurons and restores axon elongation. This effect is within axons, and the stability and function of this micro- mediated by interaction of neurofilament with the stath- tubule network is modulated by neurofilaments. Accu- min complex. Accumulating neurofilaments associate with mulation of neurofilaments has been observed in several stathmin in axons of pmn mutant motoneurons. Depletion forms of neurodegenerative diseases, but the mechanisms of neurofilament by Nefl knockout increases Stat3–stathmin how elevated neurofilament levels destabilize axons are interaction and stabilizes the microtubules in pmn mutant unknown so far. Here, we show that increased neurofila- motoneurons. Consequently, counteracting enhanced neu- ment expression in motor nerves of pmn mutant mice, a rofilament expression improves axonal maintenance and model of motoneuron disease, causes disturbed microtu- prolongs survival of pmn mutant mice. We propose that this bule dynamics. The disease is caused by a point mutation mechanism could also be relevant for other neurodegenera- in the tubulin-specific chaperone E (Tbce) gene, leading to tive diseases in which neurofilament accumulation and loss an exchange of the most C-terminal amino acid tryptophan of microtubules are prominent features. to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal Keywords Axon degeneration · Neurofilament · microtubules and defects in axonal transport, in particu- Microtubules · Stathmin · Stat3 lar in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant Introduction Electronic supplementary material The online version of this Destabilization of axon terminals and axon degenera- article (doi:10.1007/s00401-016-1564-y) contains supplementary tion are key pathological features in amyotrophic lateral material, which is available to authorized users. sclerosis (ALS) and spinal muscular atrophy (SMA), the * Michael Sendtner most common forms of motoneuron disease [6, 33, 62, [email protected] 68]. Despite progress in the identification of underlying gene defects [41, 58, 60], the cellular mechanisms that are 1 Institute of Clinical Neurobiology, University of Wuerzburg, 97078 Würzburg, Germany responsible for loss of motor function, degeneration of neu- romuscular endplates, destabilization of axons and finally 2 Institute of Anatomy and Cell Biology, University of Wuerzburg, 97070 Würzburg, Germany death of motoneuron cell bodies are not fully understood [20]. SMA and ALS are considered both clinically and 3 Department of Psychiatry and Neurosciences, Research Centre of Institut Universitaire en Santé Mentale de Québec, genetically as distinct disorders. However, they share com- University Laval, Quebec, Canada mon features. On the clinical side, dysfunction and degen- 4 Department of Biotechnology and Biophysics, University eration of neuromuscular endplates appears as an early of Wuerzburg, 97074 Würzburg, Germany symptom in both disorders, and alterations of the axonal 5 MRC Centre for Regenerative Medicine, University cytoskeleton are characteristic at early stages of both dis- of Edinburgh, Edinburgh, UK eases [16, 29, 35]. Accumulation of spheroids in proximal 1 3 94 Acta Neuropathol (2016) 132:93–110 axons is commonly observed in ALS, and these spheroids background were crossed with heterozygous Nefl knockout primarily contain neurofilaments [13, 23, 52]. In a mouse mice on a C57BL/6 genetic background [83] to produce model of SMA, the density of intermediate filaments in double heterozygous Nefl / ; pmn / mice. These mice + − + − proximal and distal axons is highly increased [9], similar were then backcrossed with NMRI genetic background for as in tg(SOD1*G93A) mutant mice [75], a model for a at least four generations to obtain a uniform NMRI genetic common form of familial ALS. This increased density of background. Subsequently, the heterozygous Nefl / ; + − neurofilaments coincides with lack of axonal sprouting and pmn / were intercrossed to obtain the mice investigated + − increased dynamics and instability of axonal microtubules in this work. NMRI genetic background was preferred [19, 22, 37, 38], indicating that the increased density of over C57BL/6 to obtain bigger litter sizes under a situation intermediate filaments and destabilization of microtubules when two autosomal recessive traits (pmn and Nefl) had to are functionally connected. be crossed to obtain the desired genotypes. Nefl knockout Neurofilaments modulate microtubule stability and thus and corresponding control wild-type mice on a C57BL/6 axon caliber and microtubule functions in axonal transport genetic background were used for the immunoprecipitation [49]. NFL is required for the assembly of neurofilaments, experiments. All experimental procedures were approved as NFM and NFH cannot form intermediate filaments in by animal care and ethic committee of the University of the absence of NFL [17, 18]. Abnormal accumulation of Wuerzburg, the Veterinäramt of the City of Wuerzburg neurofilaments causes neuronal degeneration by disrupting and the Regierung von Unterfranken, and were performed axonal transport of cargos required for the maintenance of according to the guidelines of the European Union. All axon terminals [10]. Depletion of axonal neurofilaments in mice were maintained under a 12-h light/dark cycle with Nefl / and tg(Prph);Nefl / neurons leads to improved food and water ad libitum. − − − − axonal transport of mitochondria and lysosomes [56]. It also increases life span in tg(SOD1*G85R) mutant mice Antibodies [79] and attenuates the neurodegenerative disease pheno- type in tau T44 transgenic mice [28]. However, the precise Antibodies against neurofilament-light chain Ab9035 molecular mechanisms how neurofilament depletion stabi- (Western blot), and NFL mouse monoclonal, Cat# MCA- lizes microtubules, improves axonal transport and prevents DA2 (immunostaining), tyrosinated α-tubulin (clone YL1/2; axon degeneration have remained unclear. ab6160) and stathmin-1 (clone EP1573Y; ab52630) were Here we show that NFL depletion in pmn mutant mice obtained from Abcam. The specificity of these antibodies [7, 46, 66] increases microtubule stability and delays axon and in particular the stathmin antibody has been tested in degeneration. Disruption of the Nefl gene in pmn mutant previous studies [5, 66]. After stathmin-1 knockout [5] or mice increases microtubule numbers in motor axons, and lentiviral knockdown [66] the corresponding Stathmin-1 ameliorates the disease phenotype. This effect appears to band was completely abolished in Western blots. Neurofil- be caused by interaction of NFL with a protein complex ament-heavy chain antibody (AB5539) was obtained from including stathmin and signal transducer and activator of Millipore, eIF2α (D7D3), p-STAT3Y705 (D3A7), and Stat3 transcription-3 (Stat3). Interaction of Stat3 and stathmin is (124H6) (9139S) antibodies from Cell Signaling Technol- increased upon NFL depletion. Enhanced Stat3–stathmin ogy.
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