title: 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.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
authors.forename: Lin-Xia
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
authors.forename: Xi-Yang
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, China. ghu@njmu.edu.cn.|Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu, 210023, China. ghu@njmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020170:Caspase 1 / Q000172:deficiency* / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018345:Mice, Knockout; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051033:Apoptosis Inducing Factor; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011065:Poly(ADP-ribose) Polymerases; D053179:Caspase 7; D020170:Caspase 1
keywords: Apoptosis-inducing factor; Caspase-1; Caspase-7; Dopaminergic neuron; Parkinson’s disease; Poly (ADP-ribose) polymerase 1