C. Pous, Writing -original draft: A.B.; Writing -review & editing: C. Pous, A.B.; Supervision: A.B.; Project administration: A.B.; Funding acquisition: P.A.C., A.B. Funding This work was funded by grants from INSERM -Universite?d'Evry, Association Française contre les Myopathies (18813) and Association Strumpell-Lorrain

C. , Plaud was supported by DIM Cerveau et Penseé

M. Abal, M. Piel, V. Bouckson-castaing, M. Mogensen, J. B. Sibarita et al., Microtubule release from the centrosome in migrating cells, J. Cell Biol, vol.159, pp.731-737, 2002.

F. J. Ahmad and P. W. Baas, Microtubules released from the neuronal centrosome are transported into the axon, J. Cell Sci, vol.108, pp.2761-2769, 1995.

J. S. Akella, D. Wloga, J. Kim, N. G. Starostina, S. Lyons-abbott et al., MEC-17 is an alphatubulin acetyltransferase, Nature, vol.467, pp.218-222, 2010.

R. Allison, J. R. Edgar, G. Pearson, T. Rizo, T. Newton et al., Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia, J. Cell Biol, vol.216, pp.1337-1355, 2017.

J. Atherton, A. Houdusse, and C. Moores, MAPping out distribution routes for kinesin couriers, Biol. Cell, vol.105, pp.465-487, 2013.

P. W. Baas and O. I. Mozgova, A novel role for retrograde transport of microtubules in the axon, Cytoskeleton, vol.69, pp.416-425, 2012.

C. Blackstone, C. J. O'kane, and E. Reid, Hereditary spastic paraplegias: membrane traffic and the motor pathway, Nat. Rev. Neurosci, vol.12, pp.31-42, 2011.

M. B. Burg, J. D. Ferraris, and N. I. Dmitrieva, Cellular response to hyperosmotic stresses, Physiol. Rev, vol.87, pp.1441-1474, 2007.

J. Bü-rger, N. Fonknechten, M. Hoeltzenbein, L. Neumann, E. Bratanoff et al., Hereditary spastic paraplegia caused by mutations in the SPG4 gene, Eur. J. Hum. Genet, vol.8, pp.771-776, 2000.

A. Burgo, E. Sotirakis, M. Simmler, A. Verraes, C. Chamot et al., Role of Varp, a Rab21 exchange factor and TI-VAMP/VAMP7 partner, in neurite growth, EMBO Rep, vol.10, pp.1117-1124, 2009.
URL : https://hal.archives-ouvertes.fr/hal-00441596

A. Burgo, V. Proux-gillardeaux, E. Sotirakis, P. Bun, A. Casano et al., A molecular network for the transport of the TI-VAMP/VAMP7 vesicles from cell center to periphery, Dev. Cell, vol.23, pp.166-180, 2012.
URL : https://hal.archives-ouvertes.fr/hal-00764157

P. Claudiani, E. Riano, A. Errico, G. Andolfi, and E. I. Rugarli, Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus, Exp. Cell Res, vol.309, pp.358-369, 2005.

K. R. Denton, L. Lei, J. Grenier, V. Rodionov, C. Blackstone et al., Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia, Stem Cells, vol.32, pp.414-423, 2014.

T. Eckert, D. T. Le, .. Link, S. Friedmann, L. Woehlke et al., Spastin's microtubule-binding properties and comparison to katanin, PLoS ONE, vol.7, p.50161, 2012.

T. Eckert, S. Link, D. T. Le, .. Sobczak, J. Gieseke et al., Subunit Interactions and cooperativity in the microtubulesevering AAA ATPase spastin, J. Biol. Chem, vol.287, pp.26278-26290, 2012.

A. Errico, A. Ballabio, and E. I. Rugarli, Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics, Hum. Mol. Genet, vol.11, pp.153-163, 2002.

A. Errico, P. Claudiani, M. D'addio, and E. I. Rugarli, Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon, Hum. Mol. Genet, vol.13, pp.2121-2132, 2004.

K. J. Evans, E. R. Gomes, S. M. Reisenweber, G. G. Gundersen, and B. P. Lauring, Linking axonal degeneration to microtubule remodeling by Spastinmediated microtubule severing, J. Cell Biol, vol.168, pp.599-606, 2005.

C. Fassier, A. Tarrade, L. Peris, S. Courageot, P. Mailly et al., Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice, Dis. Model. Mech, vol.6, pp.72-83, 2013.
URL : https://hal.archives-ouvertes.fr/inserm-00739394

N. Fonknechten, D. Mavel, P. Byrne, C. Davoine, C. Cruaud et al., Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia, Hum. Mol. Genet, vol.9, pp.637-644, 2000.

S. J. Haggarty, K. M. Koeller, J. C. Wong, C. M. Grozinger, and S. L. Schreiber, Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation, Proc. Natl. Acad. Sci. USA, vol.100, pp.4389-4394, 2003.

S. Havlicek, Z. Kohl, H. K. Mishra, I. Prots, E. Eberhardt et al., Gene dosagedependent rescue of HSP neurite defects in SPG4 patients' neurons, Hum. Mol. Genet, vol.23, pp.2527-2541, 2014.

J. Hazan, N. Fonknechten, D. Mavel, C. Paternotte, D. Samson et al., Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia, Nat. Genet, vol.23, pp.296-303, 1999.

C. Janke, The tubulin code: molecular components, readout mechanisms, and functions, J. Cell Biol, vol.206, pp.461-472, 2014.

S. L. Jones and T. M. Svitkina, Axon initial segment cytoskeleton: architecture, development, and role in neuron polarity, Neural Plast, p.6808293, 2016.

P. R. Kasher, K. J. De-vos, S. B. Wharton, C. Manser, E. J. Bennett et al., Direct evidence for axonal transport defects in a novel mouse model of mutant spastininduced hereditary spastic paraplegia (HSP) and human HSP patients, J. Neurochem, vol.110, pp.34-44, 2009.

B. Lacroix, J. Van-dijk, N. D. Gold, J. Guizetti, G. Aldrian-herrada et al., Tubulin polyglutamylation stimulates spastin-mediated microtubule severing, J. Cell Biol, vol.189, pp.945-954, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00509804

D. T. Le, .. Eckert, T. Woehlke, and G. , Computer simulation of assembly and co-operativity of hexameric AAA ATPases, PLoS ONE, vol.8, p.67815, 2013.

L. Leo, C. Weissmann, M. Burns, M. Kang, Y. Song et al., Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation, Hum. Mol. Genet, vol.26, pp.2321-2334, 2017.

L. Li and X. Yang, Tubulin acetylation: responsible enzymes, biological functions and human diseases, Cell. Mol. Life Sci, vol.72, pp.4237-4255, 2015.

T. Lo-giudice, F. Lombardi, F. M. Santorelli, T. Kawarai, and A. Orlacchio, Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms, Exp. Neurol, vol.261, pp.518-539, 2014.

R. Mackeh, S. Lorin, A. Ratier, N. Mejdoubi-charef, A. Baillet et al., Reactive oxygen species, AMP-activated protein kinase, and the transcription cofactor p300 regulate alpha-tubulin acetyltransferase-1 (alphaTAT-1/MEC-17)-dependent microtubule hyperacetylation during cell stress, J. Biol. Chem, vol.289, pp.11816-11828, 2014.

A. Matsuyama, T. Shimazu, Y. Sumida, A. Saito, Y. Yoshimatsu et al., In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation, EMBO J, vol.21, pp.6820-6831, 2002.

C. J. Mcdermott, A. J. Grierson, J. D. Wood, M. Bingley, S. B. Wharton et al., Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation, Ann. Neurol, vol.54, pp.748-759, 2003.

M. M. Mogensen, A. Malik, M. Piel, V. Bouckson-castaing, and M. Bornens, Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein, J. Cell Sci, vol.113, pp.3013-3023, 2000.

P. Nunes, I. Roth, P. Meda, E. Fe?aille, D. Brown et al., Ionic imbalance, in addition to molecular crowding, abates cytoskeletal dynamics and vesicle motility during hypertonic stress, Proc. Natl. Acad. Sci. USA, vol.112, pp.3104-3113, 2015.

C. D. Ochoa, T. Stevens, and R. Balczon, Cold exposure reveals two populations of microtubules in pulmonary endothelia, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.300, pp.132-138, 2011.

G. Orso, A. Martinuzzi, M. G. Rossetto, E. Sartori, M. Feany et al., Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine, J. Clin. Invest, vol.115, pp.3026-3034, 2005.

D. V. Pantakani, L. S. Swapna, N. Srinivasan, and A. U. Mannan, , 2008.

, Spastin oligomerizes into a hexamer and the mutant spastin (E442Q) redistribute the wild-type spastin into filamentous microtubule, J. Neurochem, vol.106, pp.613-624

C. Papadopoulos, G. Orso, G. Mancuso, M. Herholz, S. Gumeni et al., Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network, J. Clin. Invest, vol.11, pp.1097-1110, 2010.

G. Piperno, M. Ledizet, and X. J. Chang, Microtubules containing acetylated alpha-tubulin in mammalian cells in culture, J. Cell Biol, vol.104, pp.289-302, 1987.

C. Plaud, V. Joshi, M. Marinello, D. Pastre, T. Galli et al., Spastin regulates VAMP7-containing vesicles trafficking in cortical neurons, Biochim. Biophys. Acta, vol.1863, pp.1666-1677, 2017.
URL : https://hal.archives-ouvertes.fr/hal-02173641

N. A. Reed, D. Cai, T. L. Blasius, G. T. Jih, E. Meyhofer et al., Microtubule acetylation promotes kinesin-1 binding and transport, Curr. Biol, vol.16, pp.2166-2172, 2006.

A. Roll-mecak and R. D. Vale, The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules, Curr. Biol, vol.15, pp.650-655, 2005.

A. Roll-mecak and R. D. Vale, Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin, Nature, vol.451, pp.363-367, 2008.

S. Salinas, R. E. Carazo-salas, C. Proukakis, J. M. Cooper, A. E. Weston et al., Human spastin has multiple microtubulerelated functions, J. Neurochem, vol.95, pp.1411-1420, 2005.

A. Seitz, H. Kojima, K. Oiwa, E. M. Mandelkow, Y. H. Song et al., Single-molecule investigation of the interference between kinesin, tau and MAP2c, EMBO J, vol.21, pp.4896-4905, 2002.

J. M. Solowska and P. W. Baas, Hereditary spastic paraplegia SPG4: what is known and not known about the disease, Brain, vol.138, pp.2471-2484, 2015.

J. M. Solowska, G. Morfini, A. Falnikar, B. T. Himes, S. T. Brady et al., Quantitative and functional analyses of spastin in the nervous system: implications for hereditary spastic paraplegia, J. Neurosci, vol.28, pp.2147-2157, 2008.

J. M. Solowska, J. Y. Garbern, and P. W. Baas, Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia, Hum. Mol. Genet, vol.19, pp.2767-2779, 2010.

J. M. Solowska, M. D'rozario, D. C. Jean, M. W. Davidson, D. R. Marenda et al., Pathogenic mutation of spastin has gain-of-function effects on microtubule dynamics, J. Neurosci, vol.34, pp.1856-1867, 2014.

J. M. Solowska, A. N. Rao, and P. W. Baas, Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin, Mol. Biol. Cell, vol.28, pp.1728-1737, 2017.

K. Stamer, R. Vogel, E. Thies, E. Mandelkow, and E. Mandelkow, , 2002.

, Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress, J. Cell Biol, vol.156, pp.1051-1063

R. Takemura, S. Okabe, T. Umeyama, Y. Kanai, N. J. Cowan et al., Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau, J. Cell Sci, vol.103, pp.953-964, 1992.

K. Tsaneva-atanasova, A. Burgo, T. Galli, and D. Holcman, Quantifying neurite growth mediated by interactions among secretory vesicles, microtubules, and actin networks, Biophys. J, vol.96, pp.840-857, 2009.
URL : https://hal.archives-ouvertes.fr/hal-00503015

S. F. Van-beuningen, L. Will, M. Harterink, A. Chazeau, E. Y. Van-battum et al., TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays, Neuron, vol.88, pp.1208-1226, 2015.

S. R. White, K. J. Evans, J. Lary, J. L. Cole, and B. Lauring, Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing, J. Cell Biol, vol.176, pp.995-1005, 2007.