Hypersensitivity of DJ-1-deficient Mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and Oxidative Stress

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Mar 24

PMID 15784737

Citations 319

Authors

Raymond H Kim

Patrice D Smith

Hossein Aleyasin

Shawn Hayley

Matthew P Mount

Scott Pownall

Andrew Wakeham

Annick J You-Ten

Suneil K Kalia

Patrick Horne

David Westaway

Andres M Lozano

Hymie Anisman

David S Park

Tak W Mak

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Parkinson's disease and glucose metabolism impairment.

Chen L, Wang C, Qin L, Zhang H Transl Neurodegener. 2025; 14(1):10.

PMID: 39962629 PMC: 11831814. DOI: 10.1186/s40035-025-00467-8.

Behavioral analysis of motor and non-motor impairment in rodent models of Parkinson's disease.

Sheta R, Berard M, Musiol D, Martinez-Drudis L, Oueslati A Front Aging Neurosci. 2025; 16:1464706.

PMID: 39763579 PMC: 11701160. DOI: 10.3389/fnagi.2024.1464706.

High glucose couples DJ-1 with PTEN to activate PDGFRβ for renal proximal tubular cell injury.

Das F, Ghosh-Choudhury N, Kasinath B, Sharma K, Ghosh Choudhury G PLoS One. 2025; 20(1):e0311828.

PMID: 39761275 PMC: 11703087. DOI: 10.1371/journal.pone.0311828.

Park7 deletion leads to sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes.

Helgueta S, Heurtaux T, Sciortino A, Gui Y, Ohnmacht J, Mencke P NPJ Parkinsons Dis. 2025; 11(1):8.

PMID: 39755720 PMC: 11700157. DOI: 10.1038/s41531-024-00851-7.

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson's Disease.

Salis Torres A, Lee J, Caporali A, Semple R, Horrocks M, Macrae V Int J Mol Sci. 2024; 25(20).

PMID: 39456761 PMC: 11507255. DOI: 10.3390/ijms252010973.

References

Taira T, Saito Y, Niki T, Iguchi-Ariga S, Takahashi K, Ariga H . DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004; 5(2):213-8. PMC: 1298985. DOI: 10.1038/sj.embor.7400074. View

Bandopadhyay R, Kingsbury A, Cookson M, Reid A, Evans I, Hope A . The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain. 2003; 127(Pt 2):420-30. DOI: 10.1093/brain/awh054. View

Olzmann J, Brown K, Wilkinson K, Rees H, Huai Q, Ke H . Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function. J Biol Chem. 2003; 279(9):8506-15. DOI: 10.1074/jbc.M311017200. View

Hayley S, Crocker S, Smith P, Shree T, Jackson-Lewis V, Przedborski S . Regulation of dopaminergic loss by Fas in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Neurosci. 2004; 24(8):2045-53. PMC: 6730390. DOI: 10.1523/JNEUROSCI.4564-03.2004. View

Valente E, Abou-Sleiman P, Caputo V, Muqit M, Harvey K, Gispert S . Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004; 304(5674):1158-60. DOI: 10.1126/science.1096284. View

Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga S, Ariga H . Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients. Biochem Biophys Res Commun. 2004; 320(2):389-97. DOI: 10.1016/j.bbrc.2004.05.187. View

Tan E, Tan C, Zhao Y, Yew K, Shen H, Chandran V . Genetic analysis of DJ-1 in a cohort Parkinson's disease patients of different ethnicity. Neurosci Lett. 2004; 367(1):109-12. DOI: 10.1016/j.neulet.2004.05.090. View

Di Chiara G, Imperato A . Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A. 1988; 85(14):5274-8. PMC: 281732. DOI: 10.1073/pnas.85.14.5274. View

Tatton W, Kwan M, Verrier M, Seniuk N, Theriault E . MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells. Brain Res. 1990; 527(1):21-31. DOI: 10.1016/0006-8993(90)91056-m. View

10.

Giros B, Jaber M, Jones S, Wightman R, Caron M . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996; 379(6566):606-12. DOI: 10.1038/379606a0. View

11.

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

12.

Matsuura K, Kabuto H, Makino H, Ogawa N . Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods. 1997; 73(1):45-8. DOI: 10.1016/s0165-0270(96)02211-x. View

13.

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A . Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276(5321):2045-7. DOI: 10.1126/science.276.5321.2045. View

14.

Cheung N, Hickling Y, Beart P . Development and survival of rat embryonic mesencephalic dopaminergic neurones in serum-free, antioxidant-rich primary cultures. Neurosci Lett. 1997; 233(1):13-6. DOI: 10.1016/s0304-3940(97)00613-7. View

15.

He T, Zhou S, DA COSTA L, Yu J, Kinzler K, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A. 1998; 95(5):2509-14. PMC: 19394. DOI: 10.1073/pnas.95.5.2509. View

16.

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S . Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392(6676):605-8. DOI: 10.1038/33416. View

17.

Lang A, Lozano A . Parkinson's disease. First of two parts. N Engl J Med. 1998; 339(15):1044-53. DOI: 10.1056/NEJM199810083391506. View

18.

Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E . The ubiquitin pathway in Parkinson's disease. Nature. 1998; 395(6701):451-2. DOI: 10.1038/26652. View

19.

Hod Y, Pentyala S, Whyard T, El-Maghrabi M . Identification and characterization of a novel protein that regulates RNA-protein interaction. J Cell Biochem. 1999; 72(3):435-44. View

20.

Paisan-Ruiz C, Jain S, Evans E, Gilks W, Simon J, van der Brug M . Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004; 44(4):595-600. DOI: 10.1016/j.neuron.2004.10.023. View