Injury induced c-Jun expression and phosphorylation in the dopaminergic nigral neurons of the rat: correlation with neuronal death and modulation by glial-cell-line-derived neurotrophic factor

This study was designed to determine whether induction and phosphorylation of the transcription factor c-Jun is associated with lesion-induced death o f dopaminergic neurons of the substantia nigra pars compacta, and if this c ellular response is modulated by glial-cell-line-derived neurotrophic facto r. In adult rats, delayed dopaminergic neuron cell death induced by intrast riatal B-hydroxydopamine injection led to a marked increase in the number o f both c-Jun- and phosphorylated cJun-immunoreactive nuclei in the substant ia nigra pars compacta. The response was maximal before any significant los s of nigral neurons could be detected (on day 7 post lesion) and was confin ed to the dopaminergic neurons. Similarly, 6-hydroxydopamine lesion of the striatal dopaminergic terminals or excitotoxic lesion of the striatal targe t neurons in neonatal rats resulted in an increased number of c-Jun- and ph osphorylated cJun-immunoreactive nigral nuclei that preceded the loss of ni gral dopaminergic neurons. By contrast, after an excitotoxic lesion of the striatal target neurons in the adult rat, resulting in atrophy but not cell death of the nigral dopaminergic neurons, no upregulation of either c-Jun or phosphorylated c-Jun was found. A single injection of 10 mug of glial-ce ll-line-derived-neurotrophic factor given at day 3 after the intrastriatal 6-hydroxydopamine lesion reduced the number of c-Jun- and phosphorylated c- Jun-immunoreactive nuclei in the substantia nigra and protected the dopamin ergic neurons from the ensuing cell death. We conclude that c-Jun induction and phosphorylation! may be involved in the cellular events leading to dea th of nigral dopaminergic neurons in vivo and that this response can be mod ulated by glial-cell-line-derived-neurotrophic factor.