Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta.

There is increasing evidence that proteins normally involved in the cell cycle can regulate neuronal programmed cell death (PCD). However, it remains unknown whether cell cycle markers are expressed in normal, postmitotic, postmigratory neurons undergoing PCD in vivo. We have previously shown that natural cell death occurs postnatally in dopamine neurons of the substantia nigra pars compacta (SNpc). PCD can be induced postnatally in these neurons either by intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA) or by medial forebrain bundle (MFB) axotomy. At the time of induction of death in these models, these neurons are long postmitotic and postmigratory. We have studied three cell cycle markers in these models: 5-bromo-2'-deoxyuridine (BrdU) incorporation (a marker of S phase), cdc2 protein expression (a marker of G2 phase), and expression of MPM2 (a marker of M phase), an epitope phosphorylated by cdc2. We report here that postmitotic dopaminergic neurons undergoing PCD in the SNpc following 6-OHDA and axotomy lesions incorporate BrdU and overexpress cdc2, but do not express MPM2. This is the first in vivo evidence that postmitotic dopamine neurons of the SNpc undergoing apoptosis express markers for S phase and G2 phase. These results raise the possibility that cell cycle regulatory proteins may play a role in the demise of dopaminergic neurons in Parkinson's disease, in which PCD has been postulated to play a role.