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.