DJ-1 Interacts with and Regulates Paraoxonase-2, an Enzyme Critical for Neuronal Survival in Response to Oxidative Stress

Parsanejad, Mohammad; Bourquard, Noam; Qu, Dianbo; Zhang, Yi; Huang, Emma; Rousseaux, Maxime W.C.; Aleyasin, Hossein; Irrcher, Isabella; Callaghan, Steve; Vaillant, Dominique C.; Kim, Raymond H.; Slack, Ruth S.; Mak, Tak W.; Reddy, Srinivasa T.; Figeys, Daniel; Park, David

doi:10.1371/journal.pone.0106601

Cited by 41 publications

(34 citation statements)

References 80 publications

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“…The ability of DJ-1 to protect from oxidative stress in several cell types has been widely reported [25–28]. Mutations and deletion in the DJ-1 gene (PARK7) result in early-onset PD in patients and in loss of the entire protein or loss-of-function versions of the protein [6].…”

Section: Discussionmentioning

confidence: 99%

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Bonilha

Bell

Rayborn

et al. 2017

Free Radical Biology and Medicine

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Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both aged mice scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging.

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Section: Discussionmentioning

confidence: 99%

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Bonilha

Bell

Rayborn

et al. 2017

Free Radical Biology and Medicine

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“…These windows of susceptibility are of interest for neurodegenerative diseases, as evidence mounts for mitochondrial dysfunction and elevated oxidative stress as key mediators of diseases such as Alzheimer and Parkinson’s [17, 18, 30]. Recent data suggest that PON2 interacts directly with DJ-1 (PARK7), allowing DJ-1 to exert antioxidant properties through the regulation of PON2 [31]. Loss of function mutations in DJ-1 are associated with some familial forms of Parkinson’s disease [32], offering a potential link between PON2 and neurodegenerative disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Developmental expression of paraoxonase 2

Garrick

Dao

Laat

et al. 2016

Chemico-Biological Interactions

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Paraoxonase 2 (PON2) is a member of the paraoxonase gene family also comprising PON1 and PON3. PON2 functions as a lactonase and exhibits anti-bacterial as well as antioxidant properties. At the cellular level, PON2 localizes to the mitochondrial and endoplasmic reticulum membranes where it scavenges reactive oxygen species. PON2 is of particular interest as it is the only paraoxonase expressed in brain tissue and appears to play a critical role in mitigating oxidative stress in the brain. The aim of this study was to investigate the expression of PON2 at the protein and mRNA level in the brain and liver of mice through development to identify potential age windows of susceptibility to oxidative stress, as well as to compare expression of hepatic PON2 to expression of PON1 and PON3. Overall, PON2 expression in the brain was lower in neonatal mice and increased with age up to postnatal day (PND) 21, with a significant decrease observed at PND 30 and 60. In contrast, the liver showed continuously increasing levels of PON2 with age, similar to the patterns of PON1 and PON3. PON2 protein levels were also investigated in brain samples from non-human primates, with PON2 increasing with age up to the infant stage and decreasing at the juvenile stage, mirroring the results observed in the mouse brain. These variable expression levels of PON2 suggest that neonatal and young adult animals may be more susceptible to neurological insult by oxidants due to lower levels of PON2 in the brain.

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“…Chemical-induced oxidative stress linked to PD pathogenesis has been widely reported, particularly 6-OHDA, MPTP, paraquat and rotenone (Cantu et al, 2011;Gao et al, 2014;Lu et al, 2015b;Parsanejad et al, 2014). These chemicals mainly impair mitochondrial function such as inhibiting complex I of the electron transport chain, resulting in the production of ROS.…”

Section: Methods Of Identifying Apoptosis or Cell Deathmentioning

confidence: 99%

“…Impaired DJ-1 activity could contribute to PD pathogenesis by lacking this transnitrosylation activity and subsequently lacking the ability to prevent neuronal cell death by oxidative stress. Another study reported that DJ-1 exerted neuroprotective effects via PON2, and PON2-deficient neurons were hypersensitised to MPP-induced oxidative stress (Parsanejad et al, 2014). Furthermore, DJ-1 was characterised as a metal-binding protein able to bind to copper and toxic mercury ions in vitro and protect metal-induced cell death by oxidative stress, and this protection was lost with the PD-mutated variants of DJ-1 (Bjorkblom et al, 2013).…”

Section: Summary Of Mechanism(s)mentioning

confidence: 99%

“…The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. Chemical-induced oxidative stress linked to PD pathogenesis has been widely reported, particularly 6-OHDA, MPTP, paraquat and rotenone (Cantu et al, 2011;Gao et al, 2014;Lu et al, 2015b;Parsanejad et al, 2014). These chemicals mainly impair mitochondrial function such as inhibiting complex I of the electron transport chain, resulting in the production of ROS.…”

Section: Supporting Publications 2016: En-955 43mentioning

confidence: 99%

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Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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DJ-1 Interacts with and Regulates Paraoxonase-2, an Enzyme Critical for Neuronal Survival in Response to Oxidative Stress

Cited by 41 publications

References 80 publications

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Developmental expression of paraoxonase 2

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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