Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis.
Publication/Presentation Date
6-29-2005
Abstract
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.
Volume
25
Issue
26
First Page
6092
Last Page
6104
ISSN
1529-2401
Published In/Presented At
Carson, C., Saleh, M., Fung, F. W., Nicholson, D. W., & Roskams, A. J. (2005). Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis. The Journal of neuroscience : the official journal of the Society for Neuroscience, 25(26), 6092–6104. https://doi.org/10.1523/JNEUROSCI.0707-05.2005
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
15987939
Department(s)
Department of Pediatrics
Document Type
Article