Caspase-9 Activation Results in Downstream Caspase-8 Activation and Bid Cleavage in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinson's Disease

Abstract

Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity are both associated with dopaminergic neuron death in the substantia nigra (SN). Apoptosis has been implicated in this cell loss; however, whether or not it is a major component of disease pathology remains controversial. Caspases are a major class of proteases involved in the apoptotic process. To evaluate the role of caspases in PD, we analyzed caspase activation in MPTP-treated mice, in cultured dopaminergic cells, and in postmortem PD brain tissue. MPTP was found to elicit not only the activation of the effector caspase-3 but also the initiators caspase-8 and caspase-9, mitochondrial cytochrome c release, and Bid cleavage in the SN of wild-type mice. These changes were attenuated in transgenic mice neuronally expressing the general caspase inhibitor protein baculoviral p35. These mice also displayed increased resistance to the cytotoxic effects of the drug. MPTP-associated toxicity in culture was found temporally to involve cytochrome c release, activation of caspase-9, caspase-3, and caspase-8, and Bid cleavage. Caspase-9 inhibition prevented the activation of both caspase-3 and caspase-8 and also inhibited Bid cleavage, but not cytochrome c release. Activated caspase-8 and caspase-9 were immunologically detectable within MPP(+)-treated mesencephalic dopaminergic neurons, dopaminergic nigral neurons from MPTP-treated mice, and autopsied Parkinsonian tissue from late-onset sporadic cases of the disease. These data demonstrate that MPTP-mediated activation of caspase-9 via cytochrome c release results in the activation of caspase-8 and Bid cleavage, which we speculate may be involved in the amplification of caspase-mediated dopaminergic cell death. These data suggest that caspase inhibitors constitute a plausible therapeutic for PD.

The human carcinoembryonic antigen (CEA) GPI anchor mediates anoikis inhibition by inactivation of the intrinsic death pathway

“…t-Bid then translocates to the outer mitochondrial membrane and promotes oligomerization of Bax or Bak to facilitate release of cytochrome c and subsequent caspase-9 activation (Li et al, 1998;Luo et al, 1998). In addition, a caspase-9-mediated caspase-8 activation has been reported in certain cell systems (Cha et al, 2001;Viswanath et al, 2001). Although our results show clearly the involvement of Figure 5 PI3-K inhibition partially reverses the CEA-mediated inhibition of caspase-9 and -3 activity.…”

Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

“…This demonstrates, first, an increase in the activation of the pro-interleukin-1␤ converting enzyme (caspase-1) and, second, an increased potential for stimulating the caspase-8 activating TNF-␣ receptors on the dopaminergic neurons. This is corroborated by the increased activity of caspase-1 in substantia nigra from patients with Parkinson's disease as compared with substantia nigra from control patients (37) and by the demonstration of increased levels of activated caspase-8 in dopaminergic neurons of the substantia nigra in patients with Parkinson's disease compared with control patients (38,39). Caspase-8 is also activated in the MPTP mouse model of Parkinson's disease (38,39).…”

Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

“…Therefore, we concluded that the noncell-autonomous effect in which caspase-11 is expressed on microglia is the major effector of dopaminergic neuronal death in the acute MPTP model. Notwithstanding these findings, several studies have shown that acute MPTP treatment results in activation of caspase-3 in dopaminergic neurons (Viswanath et al, 2001). Therefore, we assume that a few caspase-11-positive dopaminergic neurons may die through the apoptotic cascade, via the cell-autonomous effect.…”