RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways

Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2008; 105(29):10244-9. DOI: 10.1073/pnas.0708518105
Source: PubMed

ABSTRACT Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.

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Available from: Mark Cookson, Aug 15, 2015
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    • "DJ-1 is ubiquitously expressed and was initially identified as a potential oncogene cooperating in the transformation activity of Ha-Ras [44]. DJ-1 has been implicated in many pathways: regulation of transcription [55] [53] [67] [52] [69], binding to RNA [21] [61], regulation of sumoylation [51], protein folding as a chaperon [50] [71] [13], and cell death [27]. The DJ-1 protein is found to be cytoprotective against oxidative stress suggesting that DJ-1 represents a sensor acting as an antioxidant and preventing apoptosis [10] [54] [70] [11] [2] [8] [35] [1]. "
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    ABSTRACT: Parkinson's disease (PD) is characterized by dopaminergic dysfunction and degeneration. DJ-1/PARK7 mutations have been linked with a familial form of early onset PD. In this study, we found that human DJ-1 wild type and the missense mutants M26I, R98Q, A104T and D149A were stable proteins in cells, only the L166P mutant was unstable. In parallel, the former were not degraded and the L166P mutant was directly degraded in vitro by proteasome-mediated endoproteolytic cleavage. Furthermore, genetic evidence in fission yeast showed the direct involvement of proteasome in the degradation of human DJ-1 L166P and the corresponding L169P mutant of SPAC22E12.03c, the human orthologue of DJ-1 in Schizosaccharomyces Pombe, as their protein levels were increased at restrictive temperature in fission yeast (mts4 and pts1-732) harboring temperature sensitive mutations in proteasomal subunits. In total, our results provide evidence that direct proteasomal endoproteolytic cleavage of DJ-1 L166P is the mechanism of degradation contributing to the loss-of-function of the mutant protein, a property not shared by other DJ-1 missense mutants associated with PD.
    Biochimica et Biophysica Acta 12/2011; 1823(2):524-33. DOI:10.1016/j.bbamcr.2011.11.010 · 4.66 Impact Factor
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    • "This protein is located in the cytosol, nucleus, and mitochondria but under conditions of oxidative stress preferentially partitions to the mitochondrial matrix and intermembranous space to mediate a protective effect [72]. This protection may also be an effect of mRNA regulation and increased translation under conditions of oxidative stress [73] [74] [75]. DJ1 knockout mice downregulated uncoupling proteins 4 and 5, impaired calcium-induced uncoupling and increased oxidant damage [76]. "
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    ABSTRACT: The identification of the etiologies and pathogenesis of Parkinson's disease (PD) should play an important role in enabling the development of novel treatment strategies to prevent or slow the progression of the disease. The last few years have seen enormous progress in this respect. Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. Abnormalities of protein metabolism including protein mis-folding and aggregation are also crucial to the pathology of PD. Genetic causes of PD have specifically highlighted the importance of mitochondrial dysfunction to PD: PINK1, parkin, DJ-1 and most recently alpha-synuclein proteins have been shown to localise to mitochondria and influence function. The turnover of mitochondria by autophagy (mitophagy) has also become a focus of attention. This review summarises recent discoveries in the contribution of mitochondrial abnormalities to PD etiology and pathogenesis.
    04/2011; 2011:159160. DOI:10.4061/2011/159160
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    • "Very recently, it has been shown that oxidized dopamine can covalently modify DJ-1 (Van Laar et al., 2009); however, whether this can affect dopamine cell degeneration is unknown. Some hints may come from the involvement of DJ-1 into many cellular functions, including evidence linking this protein to oxidative stress response—a fact well known even before the association of DJ-1 with PD (Mitsumoto et al., 2001)— mitochondrial function (Zhang et al., 2005) and transcription (Zhong and Xu, 2008), nuclear transcription (Xu et al., 2005), mRNA binding and protein interaction (Hod et al., 1999; van der Brug et al., 2008) and protein degradation (Xiong et al., 2009). "
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    ABSTRACT: The two-dimensional electrophoresis (2-DE) pattern of proteins is thought to be specifically related to the physiological or pathological condition at the moment of sample preparation. On this ground, most proteomic studies move to identify specific hallmarks for a number of different conditions. However, the information arising from these investigations is often incomplete due to inherent limitations of the technique, to extensive protein post-translational modifications and sometimes to the paucity of available samples. The meta-analysis of proteomic data can provide valuable information pertinent to various biological processes that otherwise remains hidden. Here, we show a meta-analysis of the PD protein DJ-1 in heterogeneous 2-DE experiments. The protein was shown to segregate into specific clusters associated with defined conditions. Interestingly, the DJ-1 pool from neural tissues displayed a specific and characteristic molecular weight and isoelectric point pattern. Moreover, changes in this pattern have been related to neurodegenerative processes and aging. These results were experimentally validated on human brain specimens from control subjects and PD patients. ImageJ is a public domain image processing program developed by the National Institutes of Health and is freely available at All the ImageJ macros used in this study are available as supplementary material and upon request at XLSTAT can be purchased online at at a current cost of approximately 300 EUR.
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