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The mechanisms underlying this early axonal degeneration are, however, still poorly understood. Here, we examined the effects of overexpression of human wildtype alpha-synuclein (<jats:italic>\u03b1<\/jats:italic>Syn-WT), a protein associated with PD, and its mutant variants<jats:italic>\u03b1<\/jats:italic>Syn-A30P and -A53T on neurite morphology and functional parameters in rat primary midbrain neurons (PMN). Moreover, axonal degeneration after overexpression of<jats:italic>\u03b1<\/jats:italic>Syn-WT and -A30P was analyzed by live imaging in the rat optic nerve<jats:italic>in vivo<\/jats:italic>. We found that overexpression of<jats:italic>\u03b1<\/jats:italic>Syn-WT and of its mutants A30P and A53T impaired neurite outgrowth of PMN and affected neurite branching assessed by Sholl analysis in a variant-dependent manner. Surprisingly, the number of primary neurites per neuron was increased in neurons transfected with<jats:italic>\u03b1<\/jats:italic>Syn. Axonal vesicle transport was examined by live imaging of PMN co-transfected with EGFP-labeled synaptophysin. Overexpression of all<jats:italic>\u03b1<\/jats:italic>Syn variants significantly decreased the number of motile vesicles and decelerated vesicle transport compared with control. Macroautophagic flux in PMN was enhanced by<jats:italic>\u03b1<\/jats:italic>Syn-WT and -A53T but not by<jats:italic>\u03b1<\/jats:italic>Syn-A30P. Correspondingly, colocalization of<jats:italic>\u03b1<\/jats:italic>Syn and the autophagy marker LC3 was reduced for<jats:italic>\u03b1<\/jats:italic>Syn-A30P compared with the other<jats:italic>\u03b1<\/jats:italic>Syn variants. The number of mitochondria colocalizing with LC3 as a marker for mitophagy did not differ among the groups. In the rat optic nerve, both<jats:italic>\u03b1<\/jats:italic>Syn-WT and -A30P accelerated kinetics of acute axonal degeneration following crush lesion as analyzed by<jats:italic>in vivo<\/jats:italic>live imaging. We conclude that<jats:italic>\u03b1<\/jats:italic>Syn overexpression impairs neurite outgrowth and augments axonal degeneration, whereas axonal vesicle transport and autophagy are severely altered.<\/jats:p>","DOI":"10.1038\/cddis.2015.169","type":"journal-article","created":{"date-parts":[[2015,7,9]],"date-time":"2015-07-09T12:44:42Z","timestamp":1436445882000},"page":"e1811-e1811","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Alpha-Synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons"],"prefix":"10.1038","volume":"6","author":[{"given":"J C","family":"Koch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Bitow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Haack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"d'Hedouville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-N","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"T\u00f6nges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L M A","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T M","family":"Jovin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Liman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Tatenhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"B\u00e4hr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9362-7096","authenticated-orcid":false,"given":"P","family":"Lingor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,9]]},"reference":[{"key":"BFcddis2015169_CR1","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.expneurol.2012.01.011","volume":"246","author":"RE Burke","year":"2013","unstructured":"Burke RE, O'Malley K . 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