C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts.
Functional recovery and regeneration of corticospinal tract (CST) fibers following spinal cord injury by compression or dorsal hemisection in mice was monitored after application of the enzyme-deficient Clostridium botulinum C3-protein-derived 29-amino-acid fragment C3bot(154-182). This peptide significantly improved locomotor restoration in both injury models as assessed by the open-field Basso Mouse Scale for locomotion test and Rotarod treadmill experiments. These data were supported by tracing studies showing an enhanced regenerative growth of CST fibers in treated animals as visualized by anterograde tracing. Additionally, C3bot(154-182) stimulated regenerative growth of raphespinal fibers and improved serotonergic input to lumbar alpha-motoneurons. These in vivo data were confirmed by in vitro data, showing an enhanced axon outgrowth of alpha-motoneurons and hippocampal neurons cultivated on normal or growth-inhibitory substrates after application of C3bot(154-182). The observed effects were probably caused by a non-enzymatic downregulation of active RhoA by the C3 peptide as indicated by pull-down experiments. By contrast, C3bot(154-182) did not induce neurite outgrowth in primary cultures of dorsal root ganglion cells. In conclusion, C3bot(154-182) represents a novel, promising tool to foster axonal protection and/or repair, as well as functional recovery after traumatic CNS injury.
Boato
Francesco
F
Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
Hendrix
Sven
S
Huelsenbeck
Stefanie C
SC
Hofmann
Fred
F
Grosse
Gisela
G
Djalali
Susann
S
Klimaschewski
Lars
L
Auer
Maria
M
Just
Ingo
I
Ahnert-Hilger
Gudrun
G
Höltje
Markus
M
D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D002478:Cells, Cultured; D003014:Clostridium botulinum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration; D010446:Peptide Fragments / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function; D012701:Serotonin / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000503:physiopathology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D010446:Peptide Fragments; D012701:Serotonin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein