Plaud C1, Joshi V1, Marinello M1, Pastré D1, Galli T2, Curmi PA1, Burgo A3.
1 Structure and Activity of Normal and Pathological Biomolecules, INSERM U1204, Université d' Evry, France.
2 Inserm URL U950, Institut Jacques Monod, France.
3 Structure and Activity of Normal and Pathological Biomolecules, INSERM U1204, Université d' Evry, France. Electronic address: firstname.lastname@example.org.
Alteration of axonal transport has emerged as a common precipitating factor in several neurodegenerative disorders including Human Spastic Paraplegia (HSP). Mutations of the SPAST (SPG4) gene coding for the spastin protein account for 40% of all autosomal dominant uncomplicated HSP. By cleaving microtubules, spastin regulates several cellular processes depending on microtubule dynamics including intracellular membrane trafficking. Axonal transport is fundamental for the viability of motor neurons which often have very long axons and thus require efficient communication between the cell body and its periphery. Here we found that the anterograde velocity of VAMP7 vesicles, but not that of VAMP2, two vesicular-SNARE proteins implicated in neuronal development, is enhanced in SPG4-KO neurons. We showed that this effect is associated with a slight increase of the level of acetylated tubulin in SPG4-KO neurons and correlates with an enhanced activity of kinesin-1 motors. Interestingly, we demonstrated that an artificial increase of acetylated tubulin by drugs reproduces the effect of Spastin KO on VAMP7 axonal dynamics but also increased its retrograde velocity. Finally, we investigated the effect of microtubule targeting agents which rescue axonal swellings, on VAMP7 and microtubule dynamics. Our results suggest that microtubule stabilizing agents, such as taxol, may prevent the morphological defects observed in SPG4-KO neurons no simply rescuing the altered anterograde transport to basal levels but rather by increasing the retrograde velocity of axonal cargoes.
Copyright © 2017. Published by Elsevier B.V.
Biochim Biophys Acta. 2017 Apr 6. pii: S0925-4439(17)30119-9. doi: 10.1016/j.bbadis.2017.04.007. [Epub ahead of print]
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