| Parkinson's disease (PD) is one of the most common progressive neurodegenerative movement disorders. Aging is the most risk factor in pathogenesis of PD that is estimated to affect approximately 1% of the population at 60 years of age and increased to 3% at 85. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and by the presence of Lewy bodies (LBs) and Lewy neurites in living neurons. The typical clinical features of PD include tremor at rest, rigidity, postural instability and akinesia. Most of PD patients appear to be sporadic and its etiology is incompletely clear. But in the past decade, several genes have been identified associated with familial PD. In epidemiology, approximately 10-15% of PD patients are heritable PD, mutations or deletions of PD associated genes leading to dysfunction of proteins are contributed to pathogenesis of PD and one notable distinct feature of familial PD from sporadic PD is early-onset. Although the molecular mechanisms of PD are unclear, many more lines of evidence imply that UPS (ubiquitin-proteasome system) impairment, mitochondrial dysfuction and oxidative stress are common pathways underlying the pathogenesis of PD.DJ-1/PARK7 was identified associated with PD in 2003, a homozygous deletion of exons 1-5 in a Dutch family and L166P point mutation in an Italian kindred on DJ-1 are associated with rare forms of autosomal recessive early-onset PD (EOPD). Later, others mutations on DJ-1 including exons 5-7 deletion, A104T, M26I, D149A and E64D are identified associated with EOPD. Mutations on DJ-1 gene account for almost 1-2% of all EOPD. DJ-1 is highly conserved protein and exhibits multiple functions including protecting against oxidative damage, mediating signal pathways, regulating gene transcription and possessing chaperone activity. Most studies suggest that wild-type DJ-1 is localized to both cytoplasm and nucleus, and partly localized to mitochondria, however most mutants of DJ-1 including L166P promote the localization to the mitochondria and decrease of nuclear localization. Interestingly, the mitochondrial localization of wild-type DJ-1 and its mutants are enhanced under oxidative stress conditions. The mitochondrial resident wild-type DJ-1 exhibits more stronger protective effects than cytosolic and nuclear DJ-1. These findings suggest that wild-type of DJ-1 and L166P have potential functions in mitochondria. L166P was traditionally considered as "loss of function" of wild-type DJ-1, but recently, several evidence suggested overexpression of the pathogenic mutant L166P renders cell more susceptible to cell death under the oxidative stresses, that imply L166P has toxic effects in mitochondria. However, the precise roles of DJ-1 and L166P in mitochondria remain unclear.DJ-1 was originally identified as an oncogenic protein and is highly expressed in several cancers including breast cancer, lung carcinoma, prostate cancer and ovarian carcinoma. Interestingly, in these tumors, level of autophagy and autophagy related protein Beclinl is down-regulated. And in consideration of many oncogenic proteins inhibit autophagy, DJ-1 may have potential functions in tumorigenesis through regulating autophagy. However, it is still unknown if DJ-1 could directly regulate autophagy in these cancer cells.So, in this study, we focus on the regulation of DJ-1 on autophagy in cancer cells, as well as the molecular mechanisms of DJ-1 and L166P in mitochondria. The main findings of our study include:(â… ) Knockdown of DJ-1 induces autophagy (evident by LC3 conversion, p62 degradation) through activating JNK pathway to promote Beclin 1 transcription, whereas overexpression of DJ-1 inhibits these processes. Moreover, inhibition of JNK pathway by SP600125 blocks autophagy activation and p62 degradation induced by knockdown of DJ-1. Our findings suggest that DJ-1 regulates autophagy in a JNK-dependent manner. Thus, the involvement of DJ-1 in autophagy regulation may be involved in tumorigenesis.(â…¡) We identified that a small proportion of wild-type DJ-1 and a large proportion of DJ-1(L166P) are localized in mitochondria. In normal condition, DJ-1(L166P), but not wild-type DJ-1, is co-localized and drectly interacts with Bcl-XL, whereas both wild-type DJ-1 and DJ-1(L166P) translocate to mitochondria and bind to Bcl-XL increasingly under UV irradiation. Wild-type DJ-1 stabilizes Bcl-XL through inhibiting its degradation via UPS to protect cells from UV irradiation, however, DJ-1(L166P) dissociate Bax from Bcl-XL to promote cell death. These results suggest that wild-type DJ-1 and DJ-1(L166P) have different roles in the mitochondria to mediate cell survival and death. |
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