Caspase-1 Deficiency Alleviates Dopaminergic Neuronal Death via Inhibiting Caspase-7/AIF Pathway in MPTP/p Mouse Model of Parkinson’s Disease

Abstract

Caspase family has been recognized to be involved in dopaminergic (DA) neuronal death and to exert an unfavorable role in Parkinson's disease (PD) pathology. Our previous study has revealed that caspase-1, as an important component of NLRP3 inflammasome, induces microglia-mediated neuroinflammation in the pathogenesis of PD. However, the role of caspase-1 in DA neuronal degeneration in the onset of PD remains unclear. Here, we showed that caspase-1 knockout ameliorated DA neuronal loss and dyskinesia in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model mice. We further found that caspase-1 knockout decreased MPTP/p-induced caspase-7 cleavage, subsequently inhibited nuclear translocation of poly (ADP-ribose) polymerase 1 (PARP1), and reduced the release of apoptosis-inducing factor (AIF). Consistently, we demonstrated that caspase-1 inhibitor suppressed caspase-7/PARP1/AIF-mediated apoptosis pathway by 1-methyl-4-phenylpyridinium ion (MPP) stimulation in SH-SY5Y cells. Caspase-7 overexpression reduced the protective effects of caspase-1 inhibitor on SH-SY5Y cell apoptosis. Collectively, our results have revealed that caspase-1 regulates DA neuronal death in the pathogenesis of PD in mice via caspase-7/PARP1/AIF pathway. These findings will shed new insight into the potential of caspase-1 as a target for PD therapy.

Retracted: Downregulated expression of microRNA‐329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease

“…Studies have found that miR‐30e, as an important molecular switch, controls DNA damage by modulating expression of the CDK inhibitor p21 and targeting caspase‐3 (De Santis et al, ; Sohn, Peters, Piekorz, Budach, & Janicke, ). Our results showed the increased expression of caspase‐3 companied with enhanced apoptosis of nigral dopaminergic neurons, which was in coincidence with a previous study indicating caspase family, a key modulator in PD pathology, was involved in loss of nigral dopaminergic neuronal by releasing apoptosis‐inducing factor (AIF) (Qiao et al, ). Moreover, our experiment also presented anti‐apoptotic marker Bcl‐2 was significantly decreased with the increasing apoptosis of nigral dopaminergic neurons, which was coincident with an earlier finding showing that Bcl‐2 gene expression actively participated in the degeneration of the nigrostriatal dopaminergic system in PD (Wang et al, ).…”

Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration

“…NLRP3 is elevated in the SN of PD patients and animal models [15,25,44]. Deletion and inhibition of NLRP3 or caspase-1 mitigates dopaminergic neuronal loss in mouse models of PD created by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine or transgenic overexpression of α-synuclein [15,16,[44][45][46]. Our findings that IL-1β neutralization and caspase-1 inhibition mitigated LPS-elicited dopaminergic neurodegeneration ( Figures 5 and 6) indicated that caspapse-1 activation and IL-1β release are critical for the formation of chronic neuroinflammation and development of inflammation-related dopaminergic neurodegeneration.…”

GardeninA confers neuroprotection against environmental toxin in aDrosophilamodel of Parkinson’s disease

“…Previous studies have shown that flavonoids can function as specific activators or inhibitors of caspases 44,45 . Inhibitors against different caspases have been shown to rescue neuronal deaths in several experimental PD models 41,73 .…”