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Abstract
In vivo, neuronal over-expression of the anti-apoptotic protein Bcl-2 prevents axotomy-induced
motoneuron death and prolongs life in a mouse model of familial amyotrophic lateral
sclerosis. The mechanism of these protective effects is still unknown. We have examined,
in situ, the influence of Bcl-2 over-expression on the messenger RNA level of two
pro-apoptotic, bax and cpp32, and one anti-apoptotic, bcl-xl, regulators of neuronal
death. In neonates wild-type mice, cpp32 mRNA was increased in axotomized, dying motoneurons.
No changes in bax and bcl-xl messenger RNAs expression were detected. A similar course
was observed in protected axotomized neonate motoneurons of transgenic mice over-expressing
Bcl-2. In adult wild-type mice no motoneuron death was detected one week after axotomy:
bax and cpp32 messenger RNAs were increased and bcl-xl messenger RNA was decreased.
Four weeks after the lesion, 60% of the lesioned facial motoneurons had disappeared.
In the remaining motoneurons only cpp32 messenger RNA expression was superior to control
level. In Bcl-2 transgenic mice, no axotomy-induced facial motoneurons death was detected
but the course of the neosynthesis of cell death genes messenger RNAs was similar
to wild-type mice. Bax, Bcl-x and CPP32 immunoreactivity were increased in facial
motoneurons after axotomy. Thus, fatal axotomy induces cell death genes bax and cpp32
messenger RNAs neosynthesis which is not prevented by athanatal Bcl-2 over-expression.
This suggests that the protective effect of Bcl-2 results from interactions with Bax
and CPP32 at the post-translation level without repercussion at the messenger RNA
level. Axotomy induces cell death messenger RNA neosynthesis potentially harmful at
long-term despite Bcl-2 over-expression.