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The Journal of Neuroscience, June 29, 2005, 25(26):6092-6104; doi:10.1523/JNEUROSCI.0707-05.2005

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Cellular/Molecular
Axonal Dynactin p150^Glued Transports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Christine Carson,^1 * Maya Saleh,^2 * France W. Fung,¹ Donald W. Nicholson,² and A. Jane Roskams¹

¹Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, and ²Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Montreal, Quebec, Canada H9H 3L1

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 p150^Glued, (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 p150^Glued to reveal a differential vulnerability of subpopulations of ORNs to undergo apoptosis after axonal damage and the loss of olfactory bulb target neurons.

Key words: olfactory; bulbectomy; NMDA; p75(NGFR); neoepitope; TUNEL; coimmunoprecipitation

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Received Feb 21, 2005; revised May 9, 2005; accepted May 17, 2005.

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