Inhibition of caspases protects cerebellar granule cells of the weaver mouse from apoptosis and improves behavioral phenotype.
The homozygous mouse mutant weaver exhibits a massive loss of cerebellar granule neurons postnatally. The death of these cells is associated with a single amino acid mutation in the G protein-activated inwardly rectifying potassium channel, Girk2. Evidence suggests that both the mutated Girk2 channel and the calcium channel-associated N-methyl-d-aspartate receptor play important roles in the apoptotic death of weaver cerebellar granule cells, but the downstream events associated with this process are unknown. In this study, we demonstrate that the consequences of the mutation result in caspase activation. In addition, our results show that caspase inhibition in vivo decreases caspase activation and granule cell apoptosis and significantly improves behavioral deficits associated with the weaver's phenotype.
Peng
Jun
J
Buck Institute for Age Research, Novato, California 94945, USA.
Wu
Zhijin
Z
Wu
Yongqin
Y
Hsu
Mike
M
Stevenson
Fang Feng
FF
Boonplueang
Rapee
R
Roffler-Tarlov
Suzanne K
SK
Andersen
Julie K
JK
D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002470:Cell Survival; D002531:Cerebellum / Q000166:cytology*; D058969:Contactin 2; D004789:Enzyme Activation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006720:Homozygote; D007150:Immunohistochemistry; D051379:Mice; D008818:Mice, Neurologic Mutants; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors
D061945:Caspase Inhibitors; D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; D058969:Contactin 2; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D016194:Receptors, N-Methyl-D-Aspartate; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases