c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons.


RESULTS
We investigated the possibility that c-Abl activation is involved in the progression of ALS and that c-Abl inhibition is potentially a therapeutic strategy for ALS. Using a mouse motor neuron cell line, we found that mutation of Cu/Zn-superoxide dismutase-1 (SOD1), which is one of the causative genes of familial ALS, induced the upregulation of c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. Activation of c-Abl with a concomitant increase in activated caspase-3 was observed in the lumbar spine of G93A-SOD1 transgenic mice (G93A mice), a widely used model of ALS. The survival of G93A mice was improved by oral administration of dasatinib, which also decreased c-Abl phosphorylation, inactivated caspase-3, and improved the innervation status of neuromuscular junctions. In addition, c-Abl expression in postmortem spinal cord tissues from sporadic ALS patients was increased by 3-fold compared with non-ALS patients.


CONCLUSIONS
The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.
Department of Neurology, Nagoya University Graduate School of Medicine, Tsurumai-cho, Nagoya, Japan.
Ryu
R
Katsumata
Shinsuke
S
Ishigaki
Masahisa
M
Katsuno
Kaori
K
Kawai
Jun
J
Sone
Zhe
Z
Huang
Hiroaki
H
Adachi
Fumiaki
F
Tanaka
Fumihiko
F
Urano
Gen
G
Sobue
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D000069439:Dasatinib; D004195:Disease Models, Animal; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013844:Thiazoles / Q000627:therapeutic use
D011743:Pyrimidines; D013844:Thiazoles; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016315:Proto-Oncogene Proteins c-abl; D000069439:Dasatinib