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      DJ-1 in Parkinson’s Disease: Clinical Insights and Therapeutic Perspectives

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      Author(s): 1 , * , 2
      Publication date (Electronic):
      Journal: Journal of Clinical Medicine
      Publisher: MDPI
      Keywords: DJ-1, Parkinson’s disease, biomarker, neuroprotection

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          Abstract

          Mutations in the protein DJ-1 cause autosomal recessive forms of Parkinson’s disease (PD) and oxidized DJ-1 is found in the brains of idiopathic PD individuals. While several functions have been ascribed to DJ-1 (most notably protection from oxidative stress), its contribution to PD pathogenesis is not yet clear. Here we provide an overview of the clinical research to date on DJ-1 and the current state of knowledge regarding DJ-1 characterization in the human brain. The relevance of DJ-1 as a PD biomarker is also discussed, as are studies exploring DJ-1 as a possible therapeutic target for PD and neurodegeneration.

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          DJ-1 has a role in antioxidative stress to prevent cell death.

          Takahiro Taira, Yoshiro Saito, Takeshi Niki … (2004)
          Deletion and point (L166P) mutations of DJ-1 have recently been shown to be responsible for the onset of familial Parkinson's disease (PD, PARK7). The aim of this study was to determine the role of DJ-1 in PD. We first found that DJ-1 eliminated hydrogen peroxide in vitro by oxidizing itself. We then found that DJ-1 knockdown by short interfering RNA rendered SH-SY5Y neuroblastoma cells susceptible to hydrogen peroxide-, MPP+- or 6-hydroxydopamine-induced cell death and that cells harbouring mutant forms of DJ-1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ-1. These results clearly showed that DJ-1 has a role in the antioxidative stress reaction and that mutations of DJ-1 lead to cell death, which is observed in PD.
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            Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress.

            Raymond Kim, Patrice Smith, Hossein Aleyasin … (2005)
            Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.
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              Neuroprotective Function of DJ-1 in Parkinson's Disease

              Hiroyoshi Ariga, Kazuko Takahashi-Niki, Izumi Kato … (2013)
              Parkinson's disease (PD) is caused by dopaminergic neuronal death in the substantia nigra, resulting in a reduced level of dopamine in the striatum. Oxidative stress and mitochondrial dysfunction are thought to be major causes of neurodegeneration in PD. Although genetic and environmental factors are thought to affect the onset of PD, precise mechanisms at the molecular level have not been elucidated. The DJ-1 gene is a causative gene for familial PD (park7) and also an oncogene. DJ-1 has various functions, including transcriptional regulation, antioxidative stress reaction, and chaperone, protease, and mitochondrial regulation, and its activity is regulated by its oxidative status, especially that of cysteine 106 (C106) of DJ-1. Excess oxidation of DJ-1, which renders DJ-1 inactive, has been observed in patients with sporadic PD and Alzheimer's disease, suggesting that DJ-1 also participates in the onset and pathogenesis of sporadic PD as well as familial PD. DJ-1 is also a stress sensor and its expression is increased upon various stresses, including oxidative stress. In this review, we describe functions of DJ-1 against oxidative stress and possible roles of DJ-1 in the pathogenesis of PD.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 03 September 2019
                Publication date Collection: September 2019
                Volume: 8
                Issue: 9
                Electronic Location Identifier: 1377
                Affiliations
                [1 ]School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
                [2 ]Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
                Author notes
                [* ]Correspondence: m.repici@ 123456aston.ac.uk ; Tel.: +44-(0)-121-2045-219
                Article
                Publisher ID: jcm-08-01377
                DOI: 10.3390/jcm8091377
                PMC ID: 6780414
                PubMed ID: 31484320
                SO-VID: 56e76189-9041-46a7-b0d3-4ad3332ea0c9
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 25 July 2019
                Date accepted : 30 August 2019
                Categories
                Subject: Review

                Keywords: dj-1,parkinson’s disease,biomarker,neuroprotection
                Data availability:
                Keywords: dj-1, parkinson’s disease, biomarker, neuroprotection

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