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Sci Rep. 2016 Nov 15;6:37050. doi: 10.1038/srep37050.

Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration.

Author information

1
Department of Neurology, University Medicine Göttingen, 37075 Göttingen, Germany.
2
Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
3
Institute of Clinical Chemistry, University Medicine Göttingen, 37075 Göttingen, Germany.
4
Institute for Informatics, LMU Munich, 80333 Munich, Germany.
5
Institute for X-Ray Physics, Georg-August-University Göttingen, 37077 Göttingen, Germany.
6
Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
7
Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, 44791 Bochum, Germany.

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.

PMID:
27845394
PMCID:
PMC5109185
DOI:
10.1038/srep37050
[Indexed for MEDLINE]
Free PMC Article

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