Pro-NGF secreted by astrocytes promotes motor neuron cell death.
It is well established that motor neurons depend for their survival on many trophic factors. In this study, we show that the precursor form of NGF (pro-NGF) can induce the death of motor neurons via engagement of the p75 neurotrophin receptor. The pro-apoptotic activity was dependent upon the presence of sortilin, a p75 co-receptor expressed on motor neurons. One potential source of pro-NGF is reactive astrocytes, which up-regulate the levels of pro-NGF in response to peroxynitrite, an oxidant and producer of free radicals. Indeed, motor neuron viability was sensitive to conditioned media from cultured astrocytes treated with peroxynitrite and this effect could be reversed using a specific antibody against the pro-domain of pro-NGF. These results are consistent with a role for activated astrocytes and pro-NGF in the induction of motor neuron death and suggest a possible therapeutic target for the treatment of motor neuron disease.
Domeniconi
Marco
M
Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Hempstead
Barbara L
BL
Chao
Moses V
MV
D033942:Adaptor Proteins, Vesicular Transport; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D014157:Transcription Factors; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D030421:Peroxynitrous Acid; D011498:Protein Precursors; D014157:Transcription Factors; D000099183:Sortilin; C063843:insulin gene enhancer binding protein Isl-1; C514218:pro-nerve growth factor, rat