title: Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration.
abstract: Axonal degeneration is a key initiating event in many neurological diseases. 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 in vivo through live-imaging of the rat optic nerve and in vitro 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 in vitro. In vivo, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6 hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6 hours 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.
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Jian-Nan
authors.initials: JN
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Michel
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.|Institute of Clinical Chemistry, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Lenz
authors.affiliation: Institute for Informatics, LMU Munich, 80333 Munich, Germany.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Friedel
authors.affiliation: Institute for X-Ray Physics, Georg-August-University Göttingen, 37077 Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Köster
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Zara
authors.initials: Z
authors.lastname: d'Hedouville
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.|Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, 44791 Bochum, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tönges
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.|Institute of Clinical Chemistry, University Medicine Göttingen, 37075 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
authors.affiliation: Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Koch
mesh_terms: D000208:Acute Disease; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D036341:Intercellular Signaling Peptides and Proteins; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009901:Optic Nerve Diseases / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D002154:Calpain