Differential activation of PKC delta in the substantia nigra of rats following striatal or nigral 6-hydroxydopamine lesions.
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 PKCdelta 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 PKCdelta in the SNpc of striatal-lesioned rats. Cleavage of PKCdelta 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 PKCdelta was detected in nigral-lesioned rats. These results suggest that after 6-OHDA infusion into the striatum, retrograde neurotoxicity induces caspase 3-dependent PKCdelta proteolytic activation in the cell bodies of the SNpc, implicating this kinase in the neurodegenerative process.
Hanrott
Katharine
K
Department of Biology & Biochemistry, University of Bath BA2 7AY, UK.
Murray
Tracey K
TK
Orfali
Zeina
Z
Ward
Mark
M
Finlay
Clare
C
O'Neill
Michael J
MJ
Wonnacott
Susan
S
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*
D016627:Oxidopamine; D051745:Protein Kinase C-delta