PMID- 18650325 OWN - NLM STAT- MEDLINE DCOM- 20080902 LR - 20211020 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 28 IP - 30 DP - 2008 Jul 23 TI - Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons. PG - 7467-75 LID - 10.1523/JNEUROSCI.1877-08.2008 [doi] AB - 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. FAU - Yu, Li-ying AU - Yu LY AD - Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland. FAU - Saarma, Mart AU - Saarma M FAU - Arumae, Urmas AU - Arumae U LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Amino Acid Chloromethyl Ketones) RN - 0 (Antigens, Nuclear) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (DNA-Binding Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Homeodomain Proteins) RN - 0 (Receptors, Death Domain) RN - 0 (Transcription Factors) RN - 0 (bcl-X Protein) RN - 0 (butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone) RN - 0 (enhanced green fluorescent protein) RN - 0 (homeobox protein PITX3) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 3.4.22.- (Caspases) RN - EC 3.6.4.12 (Xrcc6 protein, mouse) RN - EC 4.2.99.- (Ku Autoantigen) RN - H88EPA0A3N (Staurosporine) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Amino Acid Chloromethyl Ketones/pharmacology MH - Analysis of Variance MH - Animals MH - Animals, Newborn MH - Antigens, Nuclear/metabolism MH - Brain-Derived Neurotrophic Factor/*deficiency/pharmacology MH - Caspases/*metabolism MH - Cells, Cultured MH - DNA-Binding Proteins/metabolism MH - Dopamine/*metabolism MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation/physiology MH - Glial Cell Line-Derived Neurotrophic Factor/*deficiency/pharmacology MH - Green Fluorescent Proteins/metabolism MH - Homeodomain Proteins/metabolism MH - Immunoprecipitation MH - Ku Autoantigen MH - Mesencephalon/*cytology MH - Mice MH - Mitochondria/*physiology MH - Neurons/*metabolism MH - Receptors, Death Domain/*metabolism MH - Staurosporine/pharmacology MH - Transcription Factors/metabolism MH - Transfection/methods MH - Tyrosine 3-Monooxygenase/metabolism MH - bcl-X Protein/metabolism PMC - PMC6670859 EDAT- 2008/07/25 09:00 MHDA- 2008/09/03 09:00 PMCR- 2009/01/23 CRDT- 2008/07/25 09:00 PHST- 2008/07/25 09:00 [pubmed] PHST- 2008/09/03 09:00 [medline] PHST- 2008/07/25 09:00 [entrez] PHST- 2009/01/23 00:00 [pmc-release] AID - 28/30/7467 [pii] AID - 3377261 [pii] AID - 10.1523/JNEUROSCI.1877-08.2008 [doi] PST - ppublish SO - J Neurosci. 2008 Jul 23;28(30):7467-75. doi: 10.1523/JNEUROSCI.1877-08.2008.