Breakdown of axonal synaptic vesicle precursor transport by microglial nitric oxide.
The mechanism of axonal injury in inflammatory brain diseases is still unclear. Increased microglial production of nitric oxide (NO) is a common early sign in neuroinflammatory diseases. We found by fluorescence correlation spectroscopy that synaptophysin tagged with enhanced green fluorescence protein (synaptophysin-EGFP) moves anterogradely in axons of cultured neurons. Activated microglia focally inhibited the axonal movement of synaptophysin-EGFP in a NO synthase-dependent manner. Direct application of a NO donor to neurons resulted in inhibition of axonal transport of synaptophysin-EGFP and synaptotagmin I tagged with EGFP, mediated via phosphorylation of c-jun NH2-terminal kinase (JNK). Thus, overt production of reactive NO by activated microglia blocks the axonal transport of synaptic vesicle precursors via phosphorylation of JNK and could cause axonal and synaptic dysfunction.
Stagi
Massimiliano
M
Neuroimmunology Group, European Neuroscience Institute Göttingen, 37073 Göttingen, Germany.
Dittrich
Petra S
PS
Frank
Nadja
N
Iliev
Asparouh I
AI
Schwille
Petra
P
Neumann
Harald
H
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins
D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D016708:Synaptophysin; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; C485184:enhanced green fluorescent protein; D050857:Synaptotagmins; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases