DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med
ABSTRACT Mutations in the PARK7/DJ-1 gene are rare causes of autosomal-recessive hereditary Parkinson's disease. Loss-of-function mutations lead to the characteristic selective neurodegeneration of nigrostriatal dopaminergic neurons, which accounts for parkinsonian symptoms. Originally identified as an oncogene, DJ-1 is a ubiquitous redox-responsive cytoprotective protein with diverse functions. In addition to cell-autonomous neuroprotective roles, DJ-1 may act in a transcellular manner, being up-regulated in reactive astrocytes in chronic neurodegenerative diseases as well as in stroke. Thus, DJ-1, particularly in its oxidized form, has been recognized as a biomarker for cancer and neurodegenerative diseases. The crystal structure of DJ-1 has been solved, allowing detailed investigations of the redox-reactive center of DJ-1. Structure-function studies revealed that DJ-1 may become activated in the presence of reactive oxygen species, under conditions of oxidative stress, but also as part of physiological receptor-mediated signal transduction. DJ-1 regulates redox signaling kinase pathways and acts as a transcriptional regulator of antioxidative gene batteries. Therefore, DJ-1 is an important redox-reactive signaling intermediate controlling oxidative stress after ischemia, upon neuroinflammation, and during age-related neurodegenerative processes. Augmenting DJ-1 activity might provide novel approaches to treating chronic neurodegenerative illnesses such as Parkinson's disease and acute damage such as stroke.
- SourceAvailable from: Vera L Bonilha
[Show abstract] [Hide abstract]
- "DJ-1 is a member of the ThiJ/Pfp1 family of molecular chaperones, which are induced during oxidative stress (Corti et al., 2011). A wide body of literature has demonstrated a protective role for DJ-1 against oxidative stress through distinct pathways in diverse cellular systems (Mitsumoto and Nakagawa, 2001; Canet-Aviles et al., 2004; Taira et al., 2004; Takahashi-Niki et al., 2004; Kim et al., 2005; Park et al., 2005; Choi et al., 2006; Meulener et al., 2006; Junn et al., 2009; Kahle et al., 2009). Overall, our data are in agreement with these previous findings and confirm a role for DJ-1 in the oxidative stress response in the retina by connecting retinal abnormalities and visual dysfunction with increased oxidative stress in DJ-1-deficient mice. "
ABSTRACT: DJ-1/PARK7 mutations or deletions cause autosomal recessive early onset Parkinson's disease (PD). Thus, DJ-1 protein has been extensively studied in brain and neurons. PD patients display visual symptoms; however, the visual symptoms specifically attributed to PD patients carrying DJ-1/PARK7 mutations are not known. In this study, we analyzed the structure and physiology of retinas of 3- and 6-month-old DJ-1 knockout (KO) mice to determine how loss of function of DJ-1 specifically contributes to the phenotypes observed in PD patients. As compared to controls, the DJ-1 KO mice displayed an increase in the amplitude of the scotopic ERG b-wave and cone ERG, while the amplitude of a subset of the dc-ERG components was decreased. The main structural changes in the DJ-1 KO retinas were found in the outer plexiform layer (OPL), photoreceptors and retinal pigment epithelium (RPE), which were observed at 3 months and progressively increased at 6 months. RPE thinning and structural changes within the OPL were observed in the retinas in DJ-1 KO mice. DJ-1 KO retinas also exhibited disorganized outer segments, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased 7,8-dihydro-8-oxoguanine-labeled DNA oxidation. Accelerated outer retinal atrophy was observed in DJ-1 KO mice after selective oxidative damage induced by a single tail vein injection of NaIO3, exposing increased susceptibility to oxidative stress. Our data indicate that DJ-1-deficient retinas exhibit signs of morphological abnormalities and physiological dysfunction in association with increased oxidative stress. Degeneration of RPE cells in association with oxidative stress is a key hallmark of age-related macular degeneration (AMD). Therefore, in addition to detailing the visual defects that occur as a result of the absence of DJ-1, our data is also relevant to AMD pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.Experimental Eye Research 07/2015; DOI:10.1016/j.exer.2015.07.014 · 3.02 Impact Factor
[Show abstract] [Hide abstract]
- "The role of DJ-1 in autophagy/mitophagy is poorly understood, although it is suggested that a decrease in mitochondrial membrane potential will result in the translocation of DJ-1 to the mitochondria, where mitophagy would be initiated through mechanisms that are still unknown (Krebiehl et al., 2010; Thomas et al., 2011; Heo et al., 2012). DJ-1 has various other diverse biological implications such as its role in oncogenesis and male infertility (Kahle et al., 2009). Furthermore , it has been found to have chaperone and protease activity, enabling it to inhibit a-synuclein aggregation (Shendelman et al., 2004; Zhou & Freed, 2005). "
ABSTRACT: Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, but not of parkin-knockouts, suggesting that DJ-1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down-regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD-causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.European Journal of Neuroscience 03/2015; 41(9). DOI:10.1111/ejn.12872 · 3.67 Impact Factor
[Show abstract] [Hide abstract]
- "Besides, the localization of Park2 protein at microtubules is an important factor for its ubiquitin ligase activity toward misfolded substrates . Park5 or UCHL1 gene provides instruction to produce ubiquitin carboxyl-terminal esterase L1 enzyme, and UCHL1 is a member of deubiquitylating enzymes (DUBs) that reverse the action of ubiquitylation reactions in ubiquitin-proteosome pathway (Chen et al. 2012; Kahle et al. 2009). Park7 mRNA or also known as of DJ-1 gene is a ubiquitous redoxresponsive neuroprotective protein with diverse functions. "
ABSTRACT: Quercetin glycosides, rutin and isoquercitrin, are potent antioxidants that have been found to possess neuroprotective effect in diseases like Parkinson's and Alzheimer's disease. In the present study, we have examined the gene expression changes with rutin and isoquercitrin pretreatment on 6-hydroxydopamine (6-OHDA)-treated toxicity in rat pheochromocytoma (PC12) cells. PC12 cells were pretreated with rutin or isoquercitrin and subsequently exposed to 6-OHDA. Rutin-pretreated PC12 attenuated the Park2, Park5, Park7, Casp3, and Casp7 genes which were expressed significantly in the 6-OHDA-treated PC12 cells. Rutin upregulated the TH gene which is important in dopamine biosynthesis, but isoquercitrin pretreatment did not affect the expression of this gene. Both rutin and isoquercitrin pretreatments upregulated the ion transport and antiapoptotic genes (NSF and Opa1). The qPCR array data were further validated by qRT-PCR using four primers, Park5, Park7, Casp3, and TH. This finding suggests that changes in the expression levels of transcripts encoded by genes that participate in ubiquitin pathway and dopamine biosynthesis may be involved in Parkinson's disease.Journal of Molecular Neuroscience 08/2014; 55(3). DOI:10.1007/s12031-014-0400-x · 2.76 Impact Factor