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¹ Research Program in Molecular Neurobiology, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland
² Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland
³ Molecular and Cellular Genetic Center, Centre National Recherche Scientifique UMR 5534, University of Lyon, 69622 Villeurbanne, France
⁴ Department of Neuroscience, Neurobiology, Uppsala University, S-751 23 Uppsala, Sweden

Address correspondence to Urmas Arumäe, Institute of Biotechnology, University of Helsinki, P.O. Box 56, Viikki Biocenter, FIN-00014 Helsinki, Finland. Tel.: 358-9-19159396. Fax: 358-9-19159366. email: urmas.arumae{at}helsinki.fi

The mitochondrial death pathway is triggered in cultured sympathetic neurons by deprivation of nerve growth factor (NGF), but the death mechanisms activated by deprivation of other neurotrophic factors are poorly studied. We compared sympathetic neurons deprived of NGF to those deprived of glial cell line–derived neurotrophic factor (GDNF). In contrast to NGF-deprived neurons, GDNF-deprived neurons did not die via the mitochondrial pathway. Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-x_L did not block the death; and the mitochondrial ultrastructure was not changed. Similarly to NGF-deprived neurons, the death induced by GDNF removal is associated with increased autophagy and requires multiple lineage kinases, c-Jun and caspase-2 and -7. Serine 73 of c-Jun was phosphorylated in both NGF- and GDNF-deprived neurons, whereas serine 63 was phosphorylated only in NGF-deprived neurons. In many NGF-deprived neurons, the ultrastructure of the mitochondria was changed. Thus, a novel nonmitochondrial caspase-dependent death pathway is activated in GDNF-deprived sympathetic neurons.

Key Words: glial cell line–derived neurotrophic factor; NGF; Bax; cytochrome c; caspases

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