Medial forebrain bundle axotomy during development induces apoptosis in dopamine neurons of the substantia nigra and activation of caspases in their degenerating axons.

There is growing evidence that programmed cell death may play a role in degenerative neurologic disease. The caspases are a family of cell death proteins that mediate proteolytic cascades in the death process. Although there is clear evidence that caspases play a role in the destruction of the components of the neuronal soma, it has been controversial whether they play a role in the degeneration of axons that accompanies the death of the cell body. It is important to define the molecular mechanisms of axonal degeneration, because terminal degeneration may occur early in neurodegenerative disease. We have therefore investigated whether caspases play a role in axonal degeneration in the dopaminergic nigrostriatal system following axotomy of the median forebrain bundle during development. We find that this lesion induces apoptosis in midbrain dopaminergic neurons at the level of the cell soma. Concomitantly with this induction of apoptosis, degeneration of dopaminergic axons occurs and is characterized by the formation of axonal swellings and spheroids. Immunohistochemical analysis reveals that the activated form of caspase-3 and a caspase cleavage product of beta-actin are abundantly expressed in these degenerating fibers. We conclude that caspases are activated in degenerating dopaminergic axons as the somata undergo programmed cell death in this model. These results raise the possibility that caspase activation may occur in other programmed cell death contexts for these neurons, and, if this is so, then their inhibition may be a useful therapeutic target.