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.
Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Christine
C
Carson
Maya
M
Saleh
France W
FW
Fung
Donald W
DW
Nicholson
A Jane
AJ
Roskams
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