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

Zhang, J. N., Michel, U., Lenz, C., Friedel, C. C., Köster, S., d'Hedouville, Z., et al. (2016). Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration. Scientific Reports, 6: 37050. doi:10.1038/srep37050.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-1BD5-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-1BDC-1
Genre: Journal Article

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 Creators:
Zhang, J. N., Author
Michel, U., Author
Lenz, C.1, Author              
Friedel, C. C., Author
Köster, S., Author
d'Hedouville, Z., Author
Tönges, L., Author
Urlaub, H.1, Author              
Bähr, M., Author
Lingor, P., Author
Koch, J. C., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

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 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.

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Language(s): eng - English
 Dates: 2016-11-15
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/srep37050
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Title: Scientific Reports
Source Genre: Journal
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Pages: 15 Volume / Issue: 6 Sequence Number: 37050 Start / End Page: - Identifier: -