Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated Cu2+/Zn2+ superoxide dismutase 1. HGF prevented induction of caspase-1 and inducible nitric oxide synthase (iNOS) in motoneurons and retained the levels of the glial-specific glutamate transporter (excitatory amino acid transporter 2/glutamate transporter 1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.
Sun
Woong
W
Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, B-7, Osaka 565-0871, Japan.
Funakoshi
Hiroshi
H
Nakamura
Toshikazu
T
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate
D017228:Hepatocyte Growth Factor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D019859:Proto-Oncogene Proteins c-met