Damage to dopaminergic neurons is mediated by proliferating cell nuclear antigen through the p53 pathway under conditions of oxidative stress in a cell model of Parkinson's disease

Li,Da-Wei; Li,Guang-Ren; Zhang,Bei-Lin; Feng,Jing-Jing; Zhao,Hua

doi:10.3892/ijmm.2015.2430

Damage to dopaminergic neurons is mediated by proliferating cell nuclear antigen through the p53 pathway under conditions of oxidative stress in a cell model of Parkinson's disease

Authors:
- Da-Wei Li
- Guang-Ren Li
- Bei-Lin Zhang
- Jing-Jing Feng
- Hua Zhao
View Affiliations

Affiliations: Neuroscience Research Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: December 10, 2015 https://doi.org/10.3892/ijmm.2015.2430
Pages: 429-435

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oxidative stress is widely considered as a central event in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying the oxidative damage-mediated loss of dopaminergic neurons in PD are not yet fully understood. Accumulating evidence has indicated that oxidative DNA damage plays a crucial role in programmed neuronal cell death, and is considered to be at least partly responsible for the degeneration of dopaminergic neurons in PD. This process involves a number of signaling cascades and molecular proteins. Proliferating cell nuclear antigen (PCNA) is a pleiotropic protein affecting a wide range of vital cellular processes, including chromatin remodelling, DNA repair and cell cycle control, by interacting with a number of enzymes and regulatory proteins. In the present study, the exposure of PC12 cells to 1-methyl-4-phenylpyridinium (MPP+) led to the loss of cell viability and decreased the expression levels of PCNA in a dose- and time-dependent manner, indicating that this protein may be involved in the neurotoxic actions of MPP+ in dopaminergic neuronal cells. In addition, a significant upregulation in p53 expression was also observed in this cellular model of PD. p53 is an upstream inducer of PCNA and it has been recognized as a key contributor responsible for dopaminergic neuronal cell death in mouse models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. This indicates that MPP+-induced oxidative damage is mediated by the downregulation of PCNA through the p53 pathway in a cellular model of PD. Thus, our results may provide some novel insight into the molecular mechanisms responsible for the development of PD and provide new possible therapeutic targets for the treatment of PD.

View Figures

View References

1	Forno LS: Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol. 55:259–272. 1996. View Article : Google Scholar : PubMed/NCBI
2	Langston JW and Irwin I: MPTP: Current concepts and controversies. Clin Neuropharmacol. 9:485–507. 1986. View Article : Google Scholar : PubMed/NCBI
3	Kopin IJ and Markey SP: MPTP toxicity: implications for research in Parkinson's disease. Annu Rev Neurosci. 11:81–96. 1988. View Article : Google Scholar : PubMed/NCBI
4	Heikkila RE, Sieber BA, Manzino L and Sonsalla PK: Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse. Mol Chem Neuropathol. 10:171–183. 1989. View Article : Google Scholar : PubMed/NCBI
5	Calon F, Lavertu N, Lemieux AM, Morissette M, Goulet M, Grondin R, Blanchet PJ, Bédard PJ and Di Paolo T: Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: correlation with dopamine concentrations and dopamine transporter. Synapse. 40:225–234. 2001. View Article : Google Scholar : PubMed/NCBI
6	Chiba K, Trevor A and Castagnoli N Jr: Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun. 120:574–578. 1984. View Article : Google Scholar : PubMed/NCBI
7	Javitch JA, D'Amato RJ, Strittmatter SM and Snyder SH: Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA. 82:2173–2177. 1985. View Article : Google Scholar
8	Akaneya Y, Takahashi M and Hatanaka H: Involvement of free radicals in MPP⁺ neurotoxicity against rat dopaminergic neurons in culture. Neurosci Lett. 193:53–56. 1995. View Article : Google Scholar : PubMed/NCBI
9	Jenner P: Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov Disord. 13(Suppl 1): 24–34. 1998.PubMed/NCBI
10	Przedborski S and Vila M: The 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. Ann N Y Acad Sci. 991:189–198. 2003. View Article : Google Scholar : PubMed/NCBI
11	Segura Aguilar J and Kostrzewa RM: Neurotoxins and neurotoxic species implicated in neurodegeneration. Neurotox Res. 6:615–630. 2004. View Article : Google Scholar
12	Schapira AH and Jenner P: Etiology and pathogenesis of Parkinson's disease. Mov Disord. 26:1049–1055. 2011. View Article : Google Scholar : PubMed/NCBI
13	Zhu J and Chu CT: Mitochondrial dysfunction in Parkinson's disease. J Alzheimers Dis. 20(Suppl 2): S325–S334. 2010.PubMed/NCBI
14	Parker WD Jr, Parks JK and Swerdlow RH: Complex I deficiency in Parkinson's disease frontal cortex. Brain Res. 1189:215–218. 2008. View Article : Google Scholar
15	Jenner P and Olanow CW: The pathogenesis of cell death in Parkinson's disease. Neurology. 66(Suppl 4): S24–S36. 2006. View Article : Google Scholar : PubMed/NCBI
16	Jenner P: Oxidative stress in Parkinson's disease. Ann Neurol. 53(Suppl 3): S26–S38. 2003. View Article : Google Scholar : PubMed/NCBI
17	Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER and Mizuno Y: Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci USA. 93:2696–2701. 1996. View Article : Google Scholar : PubMed/NCBI
18	Floor E and Wetzel MG: Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenyl-hydrazine assay. J Neurochem. 70:268–275. 1998. View Article : Google Scholar : PubMed/NCBI
19	Callio J, Oury TD and Chu CT: Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains. J Biol Chem. 280:18536–18542. 2005. View Article : Google Scholar : PubMed/NCBI
20	Vila M and Przedborski S: Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci. 4:365–375. 2003. View Article : Google Scholar : PubMed/NCBI
21	Perier C, Bové J, Vila M and Przedborski S: The rotenone model of Parkinson's disease. Trends Neurosci. 26:345–346. 2003. View Article : Google Scholar : PubMed/NCBI
22	Sun SY, An CN and Pu XP: DJ-1 protein protects dopaminergic neurons against 6-OHDA/MG-132-induced neurotoxicity in rats. Brain Res Bull. 88:609–616. 2012. View Article : Google Scholar : PubMed/NCBI
23	Heikkila RE, Hess A and Duvoisin RC: Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science. 224:1451–1453. 1984. View Article : Google Scholar : PubMed/NCBI
24	Mattson MP: Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 1:120–129. 2000. View Article : Google Scholar
25	Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P and Halliwell B: Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem. 69:1196–1203. 1997. View Article : Google Scholar : PubMed/NCBI
26	Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG and Montine TJ: Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol. 154:1423–1429. 1999. View Article : Google Scholar : PubMed/NCBI
27	Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL and Dawson TM: Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetra-hydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci USA. 96:5774–5779. 1999. View Article : Google Scholar
28	Tan CK, Castillo C, So AG and Downey KM: An auxiliary protein for DNA polymerase-delta from fetal calf thymus. J Biol Chem. 261:12310–12316. 1986.PubMed/NCBI
29	Prelich G, Tan CK, Kostura M, Mathews MB, So AG, Downey KM and Stillman B: Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature. 326:517–520. 1987. View Article : Google Scholar : PubMed/NCBI
30	Burkovics P, Hajdú I, Szukacsov V, Unk I and Haracska L: Role of PCNA-dependent stimulation of 3′-phosphodiesterase and 3′-5′ exonuclease activities of human Ape2 in repair of oxidative DNA damage. Nucleic Acids Res. 37:4247–4255. 2009. View Article : Google Scholar : PubMed/NCBI
31	Amoroso A, Concia L, Maggio C, Raynaud C, Bergounioux C, Crespan E, Cella R and Maga G: Oxidative DNA damage bypass in Arabidopsis thaliana requires DNA polymerase λ and proliferating cell nuclear antigen 2. Plant Cell. 23:806–822. 2011. View Article : Google Scholar : PubMed/NCBI
32	Hirata H and Cadet JL: p53-knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies. J Neurochem. 69:780–790. 1997. View Article : Google Scholar : PubMed/NCBI
33	Duan W, Zhu X, Ladenheim B, Yu QS, Guo Z, Oyler J, Cutler RG, Cadet JL, Greig NH and Mattson MP: p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol. 52:597–606. 2002. View Article : Google Scholar : PubMed/NCBI
34	Trimmer PA, Smith TS, Jung AB and Bennett JP Jr: Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration. 5:233–239. 1996. View Article : Google Scholar : PubMed/NCBI
35	Moldovan GL, Pfander B and Jentsch S: PCNA, the maestro of the replication fork. Cell. 129:665–679. 2007. View Article : Google Scholar : PubMed/NCBI
36	Samii A, Nutt JG and Ransom BR: Parkinson's disease. Lancet. 363:1783–1793. 2004. View Article : Google Scholar : PubMed/NCBI
37	Li DW, Yao M, Dong YH, Tang MN, Chen W, Li GR and Sun BQ: Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson's disease. Int J Mol Med. 34:1358–1364. 2014.PubMed/NCBI
38	Trachootham D, Alexandre J and Huang P: Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 8:579–591. 2009. View Article : Google Scholar : PubMed/NCBI
39	Martinon F: Signaling by ROS drives inflammasome activation. Eur J Immunol. 40:616–619. 2010. View Article : Google Scholar : PubMed/NCBI
40	Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA and Ganie SA: Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother. 74:101–110. 2015. View Article : Google Scholar : PubMed/NCBI
41	He F and Zuo L: Redox roles of reactive oxygen species in cardiovascular diseases. Int J Mol Sci. 16:27770–27780. 2015. View Article : Google Scholar : PubMed/NCBI
42	Lotharius J and Brundin P: Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci. 3:932–942. 2002. View Article : Google Scholar : PubMed/NCBI
43	Montine KS, Quinn JF, Zhang J, Fessel JP, Roberts LJ II, Morrow JD and Montine TJ: Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases. Chem Phys Lipids. 128:117–124. 2004. View Article : Google Scholar : PubMed/NCBI
44	Nagatsu T and Sawada M: Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: possible implications of glial cells. J Neural Transm Suppl. 71:53–65. 2006. View Article : Google Scholar
45	Kumar MJ and Andersen JK: Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol. 30:77–89. 2004. View Article : Google Scholar : PubMed/NCBI
46	Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H and Lee VM: Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem. 280:21212–21219. 2005. View Article : Google Scholar : PubMed/NCBI
47	Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J and Lucius R: Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. Acta Neuropathol. 116:47–55. 2008. View Article : Google Scholar : PubMed/NCBI
48	Sadrzadeh SM and Saffari Y: Iron and brain disorders. Am J Clin Pathol. 121(Suppl): S64–S70. 2004.PubMed/NCBI
49	Jomova K and Valko M: Advances in metal-induced oxidative stress and human disease. Toxicology. 283:65–87. 2011. View Article : Google Scholar : PubMed/NCBI
50	Núñez MT, Urrutia P, Mena N, Aguirre P, Tapia V and Salazar J: Iron toxicity in neurodegeneration. Biometals. 25:761–776. 2012. View Article : Google Scholar : PubMed/NCBI
51	Lan J and Jiang DH: Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. J Neural Transm. 104:469–481. 1997. View Article : Google Scholar : PubMed/NCBI
52	Fang J, Seki T and Maeda H: Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev. 61:290–302. 2009. View Article : Google Scholar : PubMed/NCBI
53	Fruehauf JP and Meyskens FL Jr: Reactive oxygen species: a breath of life or death? Clin Cancer Res. 13:789–794. 2007. View Article : Google Scholar : PubMed/NCBI
54	Day BJ: Catalytic antioxidants: A radical approach to new therapeutics. Drug Discov Today. 9:557–566. 2004. View Article : Google Scholar : PubMed/NCBI
55	Nikitaki Z, Hellweg CE, Georgakilas AG and Ravanat JL: Stress-induced DNA damage biomarkers: applications and limitations. Front Chem. 3:352015. View Article : Google Scholar : PubMed/NCBI
56	Aziz K, Nowsheen S, Pantelias G, Iliakis G, Gorgoulis VG and Georgakilas AG: Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. Pharmacol Ther. 133:334–350. 2012. View Article : Google Scholar
57	Smolarz B, Wilczyński J and Nowakowska D: DNA repair mechanisms and human cytomegalovirus (HCMV) infection. Folia Microbiol (Praha). 60:199–209. 2015. View Article : Google Scholar
58	Mailand N, Gibbs-Seymour I and Bekker-Jensen S: Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol. 14:269–282. 2013. View Article : Google Scholar : PubMed/NCBI
59	Koundrioukoff S, Jónsson ZO, Hasan S, de Jong RN, van der Vliet PC, Hottiger MO and Hübscher U: A direct interaction between proliferating cell nuclear antigen (PCNA) and Cdk2 targets PCNA-interacting proteins for phosphorylation. J Biol Chem. 275:22882–22887. 2000. View Article : Google Scholar : PubMed/NCBI
60	Waga S, Hannon GJ, Beach D and Stillman B: The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 369:574–578. 1994. View Article : Google Scholar : PubMed/NCBI
61	Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh C, Davezac N, Reuter N, Mouthon L, Hermine O, et al: Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J Exp Med. 207:2631–2645. 2010. View Article : Google Scholar : PubMed/NCBI
62	Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B: A model for p53-induced apoptosis. Nature. 389:300–305. 1997. View Article : Google Scholar : PubMed/NCBI
63	Mirza A, Wu Q, Wang L, McClanahan T, Bishop WR, Gheyas F, Ding W, Hutchins B, Hockenberry T, Kirschmeier P, et al: Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene. 22:3645–3654. 2003. View Article : Google Scholar : PubMed/NCBI
64	Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI
65	Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ: Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14:981–993. 2000.PubMed/NCBI
66	Chipuk JE and Green DR: Dissecting p53-dependent apoptosis. Cell Death Differ. 13:994–1002. 2006. View Article : Google Scholar : PubMed/NCBI
67	Culmsee C and Mattson MP: p53 in neuronal apoptosis. Biochem Biophys Res Commun. 331:761–777. 2005. View Article : Google Scholar : PubMed/NCBI
68	Morris GF, Bischoff JR and Mathews MB: Transcriptional activation of the human proliferating-cell nuclear antigen promoter by p53. Proc Natl Acad Sci USA. 93:895–899. 1996. View Article : Google Scholar : PubMed/NCBI
69	Shivakumar CV, Brown DR, Deb S and Deb SP: Wild-type human p53 transactivates the human proliferating cell nuclear antigen promoter. Mol Cell Biol. 15:6785–6793. 1995z. View Article : Google Scholar