title: Elevated TRAF2/6 expression in Parkinson's disease is caused by the loss of Parkin E3 ligase activity.
abstract: Parkinson's disease (PD) is the second leading neurodegenerative disease, and is known to be induced by environmental factors or genetic mutations. Among the verified genetic mutations of PD, Parkin, isolated from the PARK2 locus, shows an autosomal recessive inheritance pattern and is known to be an E3 ligase. However, the physiological target of Parkin and the molecular mechanism of Parkin-deficiency-induced PD have not been clearly demonstrated until now. It has recently been proposed that inflammation, suggesting as a causal factor for PD, is enhanced by Parkin deficiency. Thus, we examined the relationship between inflammation-related factors and Parkin. Here, we provide the evidence that Parkin suppresses inflammation and cytokine-induced cell death by promoting the proteasomal degradation of TRAF2/6 (TNF-α receptor-associated factor 2/6). Overexpression of Parkin can reduce the half-lives of TRAF2 and TRAF6, whereas si-Parkin can extend them. However, mutant Parkins did not alter the expression of TRAF2/6. Thus, loss of Parkin enhances sensitivity to TNF-α- or IL-1β-induced JNK activation and NF-κB activation. Indeed, si-Parkin-induced apoptosis is suppressed by the knockdown of TRAF6 or TRAF2. We also observed elevated expression levels of TRAF6 and a reduction of IκB in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model. Moreover, elevated expression levels or aggregation of TRAF6 were detected in approximately half of the human PD tissues (7/15 cases) and 2 cases, respectively. In addition, TRAF6 and Parkin expression levels show a reverse relationship in human PD tissues. Our results strongly suggest that the reduction of Parkin or overexpression of TRAF2/6 by chronic inflammation would be the reason for occurrence of PD.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Chung
authors.forename: Hee Ra
authors.initials: HR
authors.lastname: Park
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Lee
authors.forename: Jin Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Youn-Sang
authors.initials: YS
authors.lastname: Jung
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Hwang
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
authors.forename: Won-Gi
authors.initials: WG
authors.lastname: Seol
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex