Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.
Petri
Susanne
S
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA. petri.susanne@mh-hannover.de
Kiaei
Mahmoud
M
Wille
Elizabeth
E
Calingasan
Noel Y
NY
Flint Beal
M
M
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D011336:Probability; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D053222:Fas Ligand Protein; C002744:3-nitrotyrosine; D014443:Tyrosine; D052248:Nitric Oxide Synthase Type I; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase