TY - JOUR
T1 - A recoverable state of axon injury persists for hours after spinal cord contusion in vivo
AU - Williams, Philip R.
AU - Marincu, Bogdan Nicolae
AU - Sorbara, Catherine D.
AU - Mahler, Christoph F.
AU - Schumacher, Adrian Minh
AU - Griesbeck, Oliver
AU - Kerschensteiner, Martin
AU - Misgeld, Thomas
N1 - Funding Information:
We would like to thank Manuela Budak, Ljiljana Marinković and Nebahat Budak for animal husbandry, Sarah Bechtold, Yvonne Hufnagel and Kristina Wullimann for technical assistance, Monika Schetterer for administrative support and Anja Schmalz for AAV production. This project was centrally supported by the Human Frontiers Science Program (individual investigator grant to P.R.W.) and the ‘Wings for Life’ Foundation (project grant to P.R.W.). Further support came from the Deutsche Forschungs-gemeinschaft (DFG) via the Center for Integrated Protein Science Munich (EXC 114; T.M.), the Munich Cluster for Systems Neurology (EXC 1010 SyNergy; M.K. and T.M.), Sonderforschungsbereich 870 (O.G., M.K. and T.M.), Schwerpunktprogramm 1710 (M.K. and T.M.) and SFB-Transregio 128 (M.K.). T.M.’s and M.K.’s laboratories are both supported by the European Research Council (‘DIABLo’ project no. 616791 and ‘NEMESIS’, project no. 310932 respectively). T.M.’s laboratory is further supported by the German Center for Neurodegenerative Disease (DZNE Munich) and the Hans-und-Ilse-Breuer Foundation, while M.K. receives support from the German Federal Ministry of Research and Education (‘Competence Network Multiple Sclerosis’) and the ‘Verein Therapieforschung für MS-Kranke e.V.’. C.D.S. was supported by the Graduate School of Technische Uni-versität München (TUM-GS), while C.M. and A.-M.S. received support from Ludwig-Maximilians University’s programme ‘Förderung Forschung und Lehre’ (FöFoLe).
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/12
Y1 - 2014/12
N2 - Therapeutic strategies for spinal cord injury (SCI) commonly focus on regenerating disconnected axons. An alternative approach would be to maintain continuity of damaged axons, especially after contusion. The viability of such neuropreservative strategies depends on the degree to which initially injured axons can recover. Here we use morphological and molecular in vivo imaging after contusion SCI in mice to show that injured axons persist in a metastable state for hours. Intra-axonal calcium dynamics influence fate, but the outcome is not invariably destructive in that many axons with calcium elevations recover homeostasis without intervention. Calcium enters axons primarily through mechanopores. Spontaneous pore resealing allows calcium levels to normalize and axons to survive long term. Axon loss can be halted by blocking calcium influx or calpain, even with delayed initiation. Our data identify an inherent self-preservation process in contused axons and a window of opportunity for rescuing connectivity after nontransecting SCI.
AB - Therapeutic strategies for spinal cord injury (SCI) commonly focus on regenerating disconnected axons. An alternative approach would be to maintain continuity of damaged axons, especially after contusion. The viability of such neuropreservative strategies depends on the degree to which initially injured axons can recover. Here we use morphological and molecular in vivo imaging after contusion SCI in mice to show that injured axons persist in a metastable state for hours. Intra-axonal calcium dynamics influence fate, but the outcome is not invariably destructive in that many axons with calcium elevations recover homeostasis without intervention. Calcium enters axons primarily through mechanopores. Spontaneous pore resealing allows calcium levels to normalize and axons to survive long term. Axon loss can be halted by blocking calcium influx or calpain, even with delayed initiation. Our data identify an inherent self-preservation process in contused axons and a window of opportunity for rescuing connectivity after nontransecting SCI.
UR - http://www.scopus.com/inward/record.url?scp=84922594767&partnerID=8YFLogxK
U2 - 10.1038/ncomms6683
DO - 10.1038/ncomms6683
M3 - Article
C2 - 25511170
AN - SCOPUS:84922594767
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 5683
ER -