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Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD <jats:italic>in vivo<\/jats:italic> through live-imaging of the rat optic nerve and <jats:italic>in vitro<\/jats:italic> in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side. A screening of calpain targets revealed that collapsin response mediator protein-2 (CRMP2) is a main downstream target of calpain activation in AAD. CRMP2-overexpression delayed bulb formation and rescued impairment of axonal mitochondrial transport after axotomy <jats:italic>in vitro. In vivo<\/jats:italic>, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6\u2009hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6\u2009hours after crush, which identified further proteins regulated during AAD, including several interactors of CRMP2. These findings reveal CRMP2 as an important mediator of AAD and define it as a putative therapeutic target.<\/jats:p>","DOI":"10.1038\/srep37050","type":"journal-article","created":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T10:39:02Z","timestamp":1479206342000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration"],"prefix":"10.1038","volume":"6","author":[{"given":"Jian-Nan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline C.","family":"Friedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"K\u00f6ster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zara","family":"d\u2019Hedouville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"T\u00f6nges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Urlaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"B\u00e4hr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Lingor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,15]]},"reference":[{"key":"BFsrep37050_CR1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/nrn1788","volume":"6","author":"M Coleman","year":"2005","unstructured":"Coleman, M. 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