期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 27, 期 5, 页码 1086-1096出版社
WILEY
DOI: 10.1111/j.1460-9568.2008.06097.x
关键词
apoptosis; caspase 3; Parkinson's disease; striatum; substantia nigra pars compacta; tyrosine hydroxylase immunoreactivity
资金
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- Parkinson's UK [G-0613] Funding Source: Medline
- Parkinson's UK [G-0613] Funding Source: researchfish
Parkinsonian neurodegeneration is associated with heightened levels of oxidative stress and the activation of apoptotic pathways. In an in vitro cellular model, we reported that 6-hydroxydopamine (6-OHDA) induces apoptotic cell death via the induction of mitochondrial dysfunction, the activation of caspase 3 and the consequent proteolytic activation of the redox-sensitive kinase, protein kinase C (PKC)delta, in PC12 cells. Here we have investigated the involvement of PKC delta in 6-OHDA-induced cell death in vivo. The nigrostriatal pathway of rats was lesioned by unilateral infusion of 6-OHDA into either the striatum or substantia nigra pars compacta (SNpc). Infusion into the SNpc resulted in rapid loss of tyrosine hydroxylase (TH)-positive cells (87% decrease after 4 days), consistent with a necrotic-like mode of cell death. In contrast, striatal infusion initiated a slower, progressive decline in TH immunoreactivity (25% decrease in the SNpc after 4 days); cell appearance was characteristic of apoptosis. This is consistent with a transient increase in active caspase 3 immunoreactivity at 4 days post-infusion, and a concomitant proteolytic activation of PKC delta in the SNpc of striatal-lesioned rats. Cleavage of PKC delta did not occur in the striatum or cerebellum of lesioned animals, or in the SNpc of sham-operated controls. No increase in caspase 3 immunoreactivity or proteolytic activation of PKC delta was detected in nigral-lesioned rats. These results suggest that after 6-OHDA infusion into the striatum, retrograde neurotoxicity induces caspase 3-dependent PKC delta proteolytic activation in the cell bodies of the SNpc, implicating this kinase in the neurodegenerative process.
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