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The Journal of Neuroscience, July 23, 2008, 28(30):7467-7475; doi:10.1523/JNEUROSCI.1877-08.2008

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Development/Plasticity/Repair
Death Receptors and Caspases But Not Mitochondria Are Activated in the GDNF- or BDNF-Deprived Dopaminergic Neurons

Li-ying Yu, Mart Saarma, and Urmas Arumäe

Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland

Correspondence should be addressed to Urmas Arumäe, Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland. Email: urmas.arumae{at}helsinki.fi

Neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote survival of midbrain dopaminergic neurons, but the death pathways activated in the dopaminergic neurons by deprivation of these factors are poorly studied. We show here that deprivation of GDNF or BDNF triggers a novel mitochondria-independent death pathway in the cultured embryonic dopaminergic neurons: cytochrome c was not released from the mitochondria to cytosol, proapoptotic protein Bax was not activated, and overexpressed Bcl-xL did not block the death. Caspases were critically required, because the death was completely blocked by caspase inhibitor BAF [boc-aspartyl(OMe)-fluoromethylketone] and overexpression of dominant-negative mutants of caspase-9, -3, and -7 significantly blocked the death. Also, the death receptor pathway was involved, because blockage of caspase-8 or FADD (Fas-associated protein with death domain), an adapter required for caspase-8 activation, inhibited death induced by GDNF or BDNF deprivation. Ligation of Fas by agonistic anti-Fas antibody induced apoptosis in the GDNF- or BDNF-maintained neurons, and inhibition of Fas by Fas-Fc chimera blocked the death of GDNF- or BDNF-deprived neurons, whereas FAIM_L (long isoform of Fas apoptosis inhibitory molecule) could control the activity of Fas in the dopaminergic neurons.

Key words: dopaminergic neurons; GDNF, BDNF; apoptosis; caspases; Fas

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Received Oct. 23, 2007; accepted May 28, 2008.

Correspondence should be addressed to Urmas Arumäe, Institute of Biotechnology, P.O. Box 56, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland. Email: urmas.arumae{at}helsinki.fi

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