Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis.
Fibroblast growth factor-1 (FGF1 or acidic FGF) is highly expressed in motor neurons. FGF-1 is released from cells by oxidative stress, which might occur from SOD-1 aberrant function in amyotrophic lateral sclerosis (ALS). Although FGF-1 is known to be neuroprotective after spinal cord injury or axotomy, we found that FGF-1 could activate spinal cord astrocytes in a manner that decreased motor neuron survival in co-cultures. FGF-1 induced accumulation of the FGF receptor 1 (FGFR1) in astrocyte nuclei and potently stimulated nerve growth factor (NGF) expression and secretion. The FGFR1 tyrosine kinase inhibitor PD166866 prevented these effects. Previously, we have shown that NGF secretion by reactive astrocytes induces motor neuron apoptosis through a p75(NTR)-dependent mechanism. Embryonic motor neurons co-cultured on the top of astrocytes exhibiting activated FGFR1 underwent apoptosis, which was prevented by PD166866 or by adding either anti-NGF or anti-p75(NTR) neutralizing antibodies. In the degenerating spinal cord of mice carrying the ALS mutation G93A of Cu, Zn superoxide dismutase, FGF-1 was no longer localized only in the cytosol of motor neurons, while FGFR1 accumulated in the nuclei of reactive astrocytes. These results suggest that FGF-1 released by oxidative stress from motor neurons might have a role in activating astrocytes, which could in turn initiate motor neuron apoptosis in ALS through a p75(NTR)-dependent mechanism.
Cassina
Patricia
P
Departamento de Histología, Facultad de Medicina, Universidad de la República Montevideo, Uruguay.
Pehar
Mariana
M
Vargas
Marcelo R
MR
Castellanos
Raquel
R
Barbeito
Ana G
AG
Estévez
Alvaro G
AG
Thompson
John A
JA
Beckman
Joseph S
JS
Barbeito
Luis
L
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3; D002452:Cell Count; D002478:Cells, Cultured; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology*; D013482:Superoxide Dismutase / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives; D014508:Urea / Q000031:analogs & derivatives
D016166:Free Radical Scavengers; D005904:Glial Fibrillary Acidic Protein; D008665:Metalloporphyrins; D011743:Pyrimidines; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D016220:Fibroblast Growth Factor 1; C002744:3-nitrotyrosine; D014443:Tyrosine; D014508:Urea; D020932:Nerve Growth Factor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; C113399:PD 166866