Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    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.
    Original languageEnglish
    JournalJournal of Neuroscience
    Volume28
    Issue number30
    Pages (from-to)7467-7475
    Number of pages9
    ISSN0270-6474
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

    Cite this

    @article{4c744b1b54854ebc8060753b2996ec8a,
    title = "Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons",
    abstract = "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.",
    author = "Liying Yu and Mart Saarma and Urmas Arum{\"a}e",
    year = "2008",
    doi = "10.1523/JNEUROSCI.1877-08.2008",
    language = "English",
    volume = "28",
    pages = "7467--7475",
    journal = "Journal of Neuroscience",
    issn = "0270-6474",
    publisher = "Society of Neuroscience",
    number = "30",

    }

    Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons. / Yu, Liying; Saarma, Mart; Arumäe, Urmas.

    In: Journal of Neuroscience, Vol. 28, No. 30, 2008, p. 7467-7475.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

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    N2 - 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.

    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.

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    M3 - Article

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