The Lurcher mutant has been extensively studied as a model for cell-autonomous and target-related cell death, yet there are still many unknowns concerning the mechanisms of neuronal degeneration in this mutant. As a key regulator of apoptosis, a bcl-2 transgene has been overexpressed in the heterozygous Lurcher mutant to investigate the effects of BCL-2 on two types of in vivo neuronal cell loss in Lurcher: cell-autonomous Purkinje cell degeneration and target-related olivary neuron death. Six

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... dult ϩ/Lc mutants expressing a human bcl-2 transgene (Hu-bcl-2) were generated by crossing ϩ/Lc mutants with NSE71 Hu-bcl-2 transgenic mice. Analysis of these brains showed that bcl-2 overexpression did not prevent ϩ/Lc Pur-kinje cell degeneration, but it did rescue most olivary neurons from target-related cell death. Although the number of olivary neurons was equivalent to wild-type numbers, the inferior olive nucleus was significantly shorter in its rostrocaudal extent, suggesting that olivary neurons are atrophied. We propose that Lurcher gene action causes Purkinje cell degeneration independently of a BCL-2-mediated pathway. Furthermore, although bcl-2 overexpression rescues olivary neurons from target-related cell death, it does not prevent the atrophy associated with the loss of target-related trophic support.