IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo.
During embryonic development, and in certain neurodegenerative diseases, neurons die by apoptosis. A new family of anti-apoptotic proteins, termed inhibitors of apoptosis (IAP), suppresses apoptosis through the direct inhibition of caspases. The anti-apoptotic activity of IAPs is inhibited by second mitochondria-derived activator of caspase (Smac)/DIABLO and XAF1 (ref. 8). IAPs, as well as neurotrophic factors, can protect degenerating neurons both in vivo and in vitro. However, the downstream targets of neurotrophic factors have not yet been identified. Here, we demonstrate that XIAP and NAIP, but not HIAP2, are directly involved in the intracellular response to glial cell-derived neurotrophic factor (GDNF). In newborn rats, GDNF regulates endogenous levels of XIAP and NAIP in motor neurons after sciatic nerve axotomy. The inhibition of XIAP or NAIP activity prevents GDNF-mediated neuroprotective effects. These results suggest that XIAP and NAIP are essential for intracellular signalling of GDNF in motor neuron survival.
Perrelet
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Division Clinical Neuromuscular Research & Department APSIC, Faculty of Medicine, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
Ferri
A
A
Liston
P
P
Muzzin
P
P
Korneluk
R G
RG
Kato
A C
AC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008159:Lumbar Vertebrae; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D051616:Neuronal Apoptosis-Inhibitory Protein; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects / Q000601:surgery; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051034:Inhibitor of Apoptosis Proteins; C496800:NAIP protein, human; C496803:Naip6 protein, rat; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D018696:Neuroprotective Agents; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494837:Xiap protein, rat