BCL-2 SENSITIVITY DIFFERENTIATES 2 PATHWAYS FOR MOTONEURONAL DEATH INTHE WOBBLER MUTANT MOUSE

The molecular events leading to motoneuronal death are still poorly un derstood. In mammals, the bcl-2 proto-oncogene, which encodes a membra ne-associated protein, has been shown to suppress both developmental m otoneuronal death and experimental axotomy-induced motoneuronal death. We assessed a potential protective effect of Bcl-2 on pathological mo toneuronal death processes in adult rodents. We took advantage of the murine mutant wobbler, which undergoes progressive degeneration of the spinal and brainstem motoneurons. A hybrid carrying both the wobbler mutation and the human bcl-2 transgene under the control of the neuron -specific enolase promoter was produced. Although Bcl-2 protected spin al and brainstem motoneurons from developmental death and the postnata l motoneurons of the facial nucleus from axotomy-induced death, the pa thological motoneuronal death was not altered in the adult hybrid. The se results demonstrate that Bcl-2 sensitivity distinguishes at least t wo different motoneuronal death pathways in the wobbler mutant. They s upport the hypothesis that experimental and pathological motoneuronal death are dependent on different cellular mechanisms.