Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson’s disease patients

Saito, Yoshiro; Akazawa-Ogawa, Yoko; Matsumura, Akihiro; Saigoh, Kazumasa; Itoh, Sayoko; Sutou, Kenta; Kobayashi, Mitsuyuki; Mita, Yuichiro; Shichiri, Mototada; Hisahara, Shin; Hara, Yasuo; Fujimura, Harutoshi; Takamatsu, Hiroyuki; Hagihara, Yoshihisa; Yoshida, Yasukazu; Hamakubo, Takao; Kusunoki, Susumu; Shimohama, Shun; Noguchi, Noriko

doi:10.1038/srep30793

Cited by 31 publications

(27 citation statements)

References 49 publications

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“…DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys106) under oxidative stress. oxDJ-1 is transformed into dimer and polymer forms that interact with 20S proteasome [70]. …”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

451

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

451

300

View full text Add to dashboard Cite

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“…Since first identified as an oncogene 2 , DJ-1 function has been the focus of several hundred studies, many of which have revealed the pleiotropic nature of the protein. For example, DJ-1 has been proposed to function as a regulator of the 20S proteasome 3 – 5 , a chaperone for alpha-synuclein 6 , a regulator of the androgen receptor 7 , a redox-sensitive esterase 8 , a peroxiredoxin-like peroxidase that scavenges H 2 O 2 9 , a transcriptional regulator 10 , an RNA binding protein 11 , a regulator of tyrosine hydroxylase 12 , a protease 13 , a stabilizer of the antioxidant transcriptional regulator Nrf2 14 , a regulator of Bax 15 , and a transcriptional regulator of uncoupling (UCP) proteins 16 . Moreover, multiple lines of evidence, including genetic studies in model organisms, have suggested DJ-1 dysfunction sensitizes cells to oxidative stress and causes mitochondrial dysfunction 3 , 17 – 26 .…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro

Matsuda

Kimura

Queliconi

et al. 2017

Sci Rep

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DJ-1 (also known as PARK7) has been identified as a causal gene for hereditary recessive Parkinson’s disease (PD). Consequently, the full elucidation of DJ-1 function will help decipher the molecular mechanisms underlying PD pathogenesis. However, because various, and sometimes inconsistent, roles for DJ-1 have been reported, the molecular function of DJ-1 remains controversial. Recently, a number of papers have suggested that DJ-1 family proteins are involved in aldehyde detoxification. We found that DJ-1 indeed converts methylglyoxal (pyruvaldehyde)-adducted glutathione (GSH) to intact GSH and lactate. Based on evidence that DJ-1 functions in mitochondrial homeostasis, we focused on the possibility that DJ-1 protects co-enzyme A (CoA) and its precursor in the CoA synthetic pathway from aldehyde attack. Here, we show that intact CoA and β-alanine, an intermediate in CoA synthesis, are recovered from methylglyoxal-adducts by recombinant DJ-1 purified from E. coli. In this process, methylglyoxal is converted to L-lactate rather than the D-lactate produced by a conventional glyoxalase. PD-related pathogenic mutations of DJ-1 (L10P, M26I, A104T, D149A, and L166P) impair or abolish detoxification activity, suggesting a pathological significance. We infer that a key to understanding the biological function of DJ-1 resides in its methylglyoxal-adduct hydrolase activity, which protects low-molecular thiols, including CoA, from aldehydes.

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“…Under physiological conditions it has been shown to form homodimers ( Fig. 1A) but higher-order assemblies have been also identified in vitro [15] and in vivo [11,16]. DJ-1 contains a crucial cysteine residue (Cys106) that is buried deep in the putative binding site with a strained dihedral conformation.…”

Section: Introductionmentioning

confidence: 99%

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Kingsford-Adaboh

Zhu²,

Jójárt

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, S), oxidized (Cys106, SO), and over-oxidized (Cys106, SO) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

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Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson’s disease patients

Cited by 31 publications

References 49 publications

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Parkinson’s disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

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