OVEREXPRESSION OF A HU-BCL-2 TRANSGENE IN LURCHER MUTANT MICE DELAYS PURKINJE-CELL DEATH

Cerebellar Purkinje cells in the heterozygous Lurcher mutant undergo c ell autonomous degeneration beginning in the second week of postnatal development and becoming almost total around 30-45 days. The Lurcher m utation was recently identified as gain-of-function defect in the delt a 2 glutamate receptor causing a constitutive current leak, suggesting that +/Lc Purkinje cells die by an excitotoxic mechanism. In previous studies we have shown that overexpression of bcl-2, a key regulator o f cell death, in the heterozygous Lurcher mutant does not prevent +/Lc Purkinje cell death. To investigate further the mechanisms of +/Lc Pu rkinje cell death, we have crossed +/Lc mutants with a second line of Hu-bcl-2 transgenics (NSE73a) that shows an earlier onset of transgene expression and higher expression levels. Analysis of eight +/Lc-NSE73 a mutants (4 at 2 months and 4 at 5-6 months) showed that Hu-bcl-2 ove rexpression delayed, but ultimately could not prevent +/Lc Purkinje ce ll death. ((C) Academie des sciences/Elsevier, Paris.).