GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway.
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-xL 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.
Yu
Li-Ying
LY
Research Program in Molecular Neurobiology, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland.
Jokitalo
Eija
E
Sun
Yun-Fu
YF
Mehlen
Patrick
P
Lindholm
Dan
D
Saarma
Mart
M
Arumae
Urmas
U
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C505533:FADD protein, human; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D018124:Receptors, Tumor Necrosis Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D020932:Nerve Growth Factor; D020169:Caspases