Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis.
Olfactory receptor neurons (ORNs) undergo caspase-mediated retrograde apoptosis after target removal (bulbectomy), in which axonal caspase-9 and caspase-3 activation leads to terminal apoptosis in ORN soma of the olfactory epithelium. Here, we show that caspase-8 can act as an initiator of ORN apoptosis after bulbectomy and also after synaptic instability is induced by NMDA-mediated excitotoxic death of ORN target neurons in the olfactory bulb. Caspase-8 and caspase-3 are sequentially activated within ORN presynaptic terminals, and caspase-8 complexes with dynactin p150Glued, (a retrograde motor protein) and is transported retrogradely, preceding axonal caspase-3 activation and apoptosis of ORN cell bodies. Focal in vivo inhibition of initiator caspase activation or microtubule-dependent transport (with Taxol) at the lesioned axon terminus results in a significant reduction in retrograde axonal caspase-8 and caspase-3 activation and inhibition of retrograde ORN death. Caspase-8 activation and retrograde transport after NMDA lesion is similarly reduced in mice null for p75, the low-affinity nerve growth factor receptor. The retrograde apoptosis of ORNs thus involves a novel mechanism that used p75 in the local activation of caspase-8. Once caspase-8 is maximally activated in the presynaptic terminal, it is transported retrogradely by the motor complex dynactin/dynein, a process that can be inhibited focally to inhibit ORN apoptosis after acute axonal lesion. These data have revealed a novel mechanism of retrograde apoptosis, in which caspase-8 complexes directly with axonal dynactin p150Glued to reveal a differential vulnerability of subpopulations of ORNs to undergo apoptosis after axonal damage and the loss of olfactory bulb target neurons.
Carson
Christine
C
Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Saleh
Maya
M
Fung
France W
FW
Nicholson
Donald W
DW
Roskams
A Jane
AJ
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D000072159:Dynactin Complex; D004558:Electric Stimulation; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D018034:Olfactory Receptor Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D000109:Acetylcholine