Bcl-2 expression using retrograde transport of adenoviral vectors inhibits cytochrome c-release and caspase-1 activation in motor neurons of mutant superoxide dismutase 1 (G93A) transgenic mice.
We explored a possible mechanism of the neuro-protective effects of exogenous human Bcl-2 expression on motor neurons of transgenic mice expressing human Cu/Zn superoxide dismutase with a G93A mutation (G93A mice), using retrograde transport and a Cre-loxP recombination system employing adenoviral vectors. We examined the cellular localization of cytochrome c and caspase-1 using immunohistochemical study, in motor neurons of hypoglossal nuclei of G93A mice at 15 weeks after inoculation with the adenoviral vectors, at which time over-expressed exogenous Bcl-2 declined to reach the baseline of intrinsic Bcl-2. We found that a significant number of neurons showed more faint and punctate immunostaining against cytochrome c and significantly less neurons showed immunoreactivity against activated caspase-1, compared with those of mice without inoculation. These results suggest that transient exogenous Bcl-2 expression at the early stage of the disease protects against motor neuronal degeneration in G93A mice by retarding translocation of cytochrome c into the cytosol, and regulating caspase-1 for a substantial period.
Yamashita
Satoshi
S
Department of Neurology, Kumamoto University, School of Medicine, 1-1-1 Honjo, Kumamoto 860-0811, Japan.
Mita
Shuji
S
Kato
Shinsuke
S
Okado
Haruo
H
Ohama
Eisaku
E
Uchino
Makoto
M
D000256:Adenoviridae / Q000235:genetics; D000409:Alanine / Q000235:genetics; D000818:Animals; D001370:Axonal Transport; D001933:Brain Stem / Q000378:metabolism / Q000821:virology; D020170:Caspase 1 / Q000378:metabolism*; D002452:Cell Count; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019426:Integrases; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014764:Viral Proteins
D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; D014764:Viral Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C045073:Cre recombinase; D019426:Integrases; D020170:Caspase 1; D000409:Alanine; D005998:Glycine