DJ-1 Protects the Nigrostriatal Axis from the Neurotoxin MPTP by Modulation of the AKT Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 6

PMID 20133695

Citations 80

Authors

Hossein Aleyasin

Maxime W C Rousseaux

Paul C Marcogliese

Sarah J Hewitt

Isabella Irrcher

Alvin P Joselin

Mohammad Parsanejad

Raymond H Kim

Patrizia Rizzu

Steve M Callaghan

Ruth S Slack

Tak W Mak

David S Park

Affiliations

Soon will be listed here.

Abstract

Loss-of-function DJ-1 (PARK7) mutations have been linked with a familial form of early onset Parkinson disease. Numerous studies have supported the role of DJ-1 in neuronal survival and function. Our initial studies using DJ-1-deficient neurons indicated that DJ-1 specifically protects the neurons against the damage induced by oxidative injury in multiple neuronal types and degenerative experimental paradigms, both in vitro and in vivo. However, the manner by which oxidative stress-induced death is ameliorated by DJ-1 is not completely clear. We now present data that show the involvement of DJ-1 in modulation of AKT, a major neuronal prosurvival pathway induced upon oxidative stress. We provide evidence that DJ-1 promotes AKT phosphorylation in response to oxidative stress induced by H(2)O(2) in vitro and in vivo following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Moreover, we show that DJ-1 is necessary for normal AKT-mediated protective effects, which can be bypassed by expression of a constitutively active form of AKT. Taken together, these data suggest that DJ-1 is crucial for full activation of AKT upon oxidative injury, which serves as one explanation for the protective effects of DJ-1.

Citing Articles

Neuroprotective role and mechanistic insights of DJ-1 dimerization in Parkinson's disease.

Lv L, Zhang H, Tan J, Wang C Cell Commun Signal. 2025; 23(1):129.

PMID: 40065349 PMC: 11892234. DOI: 10.1186/s12964-025-02136-9.

Accelerated Sarcopenia Phenotype in the DJ-1/-Knockout Zebrafish.

Rostad K, Trognitz T, Froyset A, Bifulco E, Fladmark K Antioxidants (Basel). 2025; 13(12.

PMID: 39765837 PMC: 11673048. DOI: 10.3390/antiox13121509.

Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias.

Oh C, Nakamura T, Zhang X, Lipton S Neuron. 2024; 112(23):3823-3850.

PMID: 39515322 PMC: 11624102. DOI: 10.1016/j.neuron.2024.10.013.

Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.

Bartman S, Coppotelli G, Ross J Curr Issues Mol Biol. 2024; 46(3):1987-2026.

PMID: 38534746 PMC: 10969191. DOI: 10.3390/cimb46030130.

Involvement of DJ-1 in the pathogenesis of intervertebral disc degeneration via hexokinase 2-mediated mitophagy.

Lin J, Wang L, Wu Y, Xiang Q, Zhao Y, Zheng X Exp Mol Med. 2024; 56(3):747-759.

PMID: 38531963 PMC: 10984922. DOI: 10.1038/s12276-024-01196-0.

References

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

Sun H, Lesche R, Li D, Liliental J, Zhang H, Gao J . PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1999; 96(11):6199-204. PMC: 26859. DOI: 10.1073/pnas.96.11.6199. View

Kim R, Smith P, Aleyasin H, Hayley S, Mount M, Pownall S . Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A. 2005; 102(14):5215-20. PMC: 555037. DOI: 10.1073/pnas.0501282102. View

Crossthwaite A, Hasan S, Williams R . Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J Neurochem. 2002; 80(1):24-35. DOI: 10.1046/j.0022-3042.2001.00637.x. View

Lee H, Kim M, Kim H, Kim S . Human neural stem cells genetically modified to overexpress Akt1 provide neuroprotection and functional improvement in mouse stroke model. PLoS One. 2009; 4(5):e5586. PMC: 2679145. DOI: 10.1371/journal.pone.0005586. View

Kohn A, Takeuchi F, Roth R . Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem. 1996; 271(36):21920-6. DOI: 10.1074/jbc.271.36.21920. View

Xiromerisiou G, Hadjigeorgiou G, Papadimitriou A, Katsarogiannis E, Gourbali V, Singleton A . Association between AKT1 gene and Parkinson's disease: a protective haplotype. Neurosci Lett. 2008; 436(2):232-4. PMC: 8958471. DOI: 10.1016/j.neulet.2008.03.026. View

Meier R, Alessi D, Cron P, Andjelkovic M, Hemmings B . Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem. 1997; 272(48):30491-7. DOI: 10.1074/jbc.272.48.30491. View

Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E . Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2002; 299(5604):256-9. DOI: 10.1126/science.1077209. View

10.

Inden M, Taira T, Kitamura Y, Yanagida T, Tsuchiya D, Takata K . PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson's disease rat model. Neurobiol Dis. 2006; 24(1):144-58. DOI: 10.1016/j.nbd.2006.06.004. View

11.

Wilson M, St Amour C, Collins J, Ringe D, Petsko G . The 1.8-A resolution crystal structure of YDR533Cp from Saccharomyces cerevisiae: a member of the DJ-1/ThiJ/PfpI superfamily. Proc Natl Acad Sci U S A. 2004; 101(6):1531-6. PMC: 341769. DOI: 10.1073/pnas.0308089100. View

12.

Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Ariga H . DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun. 1997; 231(2):509-13. DOI: 10.1006/bbrc.1997.6132. View

13.

Takahashi K, Taira T, Niki T, Seino C, Ariga H . DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem. 2001; 276(40):37556-63. DOI: 10.1074/jbc.M101730200. View

14.

Lavara-Culebras E, Paricio N . Drosophila DJ-1 mutants are sensitive to oxidative stress and show reduced lifespan and motor deficits. Gene. 2007; 400(1-2):158-65. DOI: 10.1016/j.gene.2007.06.013. View

15.

Lev N, Ickowicz D, Barhum Y, Lev S, Melamed E, Offen D . DJ-1 protects against dopamine toxicity. J Neural Transm (Vienna). 2008; 116(2):151-60. DOI: 10.1007/s00702-008-0134-4. View

16.

Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H, Mizusawa H . Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun. 2003; 312(4):1342-8. DOI: 10.1016/j.bbrc.2003.11.056. View

17.

Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco T, Thomas B . DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A. 2007; 104(37):14807-12. PMC: 1976193. DOI: 10.1073/pnas.0703219104. View

18.

Heo S, Han A, Kwon Y, Joung I . p62 protects SH-SY5Y neuroblastoma cells against H2O2-induced injury through the PDK1/Akt pathway. Neurosci Lett. 2008; 450(1):45-50. DOI: 10.1016/j.neulet.2008.11.011. View

19.

Park J, Kim S, Cha G, Lee S, Kim S, Chung J . Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction. Gene. 2005; 361:133-9. DOI: 10.1016/j.gene.2005.06.040. View

20.

Yang Y, Gehrke S, Haque M, Imai Y, Kosek J, Yang L . Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci U S A. 2005; 102(38):13670-5. PMC: 1224636. DOI: 10.1073/pnas.0504610102. View