Background: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein α-synuclein (α-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by α-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA). Objective: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. Methods: We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration. Results: We found that in PC12/TetOn cells overexpressing α-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased α-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of α-syn (TAT-α-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-α-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain. Conclusion: DJ-1 appears to have a protective role against dopaminergic degeneration triggered by α-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.

Keywords:
α-Synuclein, DJ-1 protein, 6-Hydroxydopamine, Parkinsonߣs disease, Therapy
1.
Di Monte DA: The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2003;2:531-538.
2.
Fahn S: Description of Parkinson's disease as a clinical syndrome. Ann NY Acad Sci 2003;991:1-14.
3.
Hardy J, Cookson MR, Singleton A: Genes and parkinsonism. Lancet Neurol 2003;2:221-228.
4.
Gosal D, Ross OA, Toft M: Parkinson's disease: the genetics of a heterogeneous disorder. Eur J Neurol 2006;13:616-627.
5.
Klein C, Schlossmacher MG: The genetics of Parkinson disease: implications for neurological care. Nat Clin Pract Neurol 2006;2:136-146.
6.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045-2047.
7.
Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998;18:106-108.
8.
Abeliovich A, Flint Beal M: Parkinsonism genes: culprits and clues. J Neurochem 2006;99:1062-1072.
9.
Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, Zhu Z, Ma H, Pan Q, Xia JH, Xia K, Zhang Z: Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum Mol Genet 2006;15:1816-1825.
10.
Jellinger KA: The morphological basis of mental dysfunction in Parkinson's disease. J Neurol Sci 2006;248:167-172.
11.
Volles MJ, Lansbury PT: Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 2003;42:7871-7878.
12.
Klucken J, Outeiro TF, Nguyen P, McLean PJ, Hyman BT: Detection of novel intracellular alpha-synuclein oligomeric species by fluorescence lifetime imaging. FASEB J 2006;20:2050-2057.
13.
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L: Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000;287:1265-1269.
14.
Fleming SM, Fernagut P-O, Chesselet MF: Genetic mouse models of parkinsonism: strengths and limitations. NeuroRx 2005;2:495-503.
15.
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K: Alpha-synuclein locus triplication causes Parkinson's disease. Science 2003;302:841.
16.
Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N: Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 2006;59:298-309.
17.
Lykkebo S, Jensen PH: Alpha-synuclein and presynaptic function: implications for Parkinson's disease. Neuromol Med 2002;2:115-129.
18.
Wersinger C, Prou D, Vernier P, Niznik HB, Sidhu A: Mutations in the lipid-binding domain of alpha-synuclein confer overlapping, yet distinct, functional properties in the regulation of dopamine transporter activity. Mol Cell Neurosci 2003;24:91-105.
19.
Ahn M, Kim S, Kang M, Ryu Y, Kim TD: Chaperone-like activities of alpha-synuclein: alpha-synuclein assists enzyme activities of esterases. Biochem Biophys Res Commun 2006;346:1142-1149.
20.
Chandra S, Fornai F, Kwon H-B, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Südhof TC: Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A 2004;101:14966-14971.
21.
Bonifati V, Oostra BA, Heutink P: Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease. J Mol Med (Berl) 2004;82:163-174.
22.
Hedrich K, Djarmati A, Schäfer N, Hering R, Wellenbrock C, Weiss PH, Hilker R, Vieregge P, Ozelius LJ, Heutink P, Bonifati V, Schwinger E, Lang AE, Noth J, Bressman SB, Pramstaller PP, Riess O, Klein C: DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology 2004;62:389-394.
23.
Eerola J, Hernandez D, Launes J, Hellström O, Hague S, Gulick C, Johnson J, Peuralinna T, Hardy J, Tienari PJ, Singleton AB: Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD. Neurology 2003;61:1000-1002.
24.
Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE, Gearing M, Levey AI, Chin LS, Li L: Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 2006;281:10816-10824.
25.
Menzies FM, Yenisetti SC, Min K-T: Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 2005;15:1578-1582.
26.
Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J, Yang L, Beal MF, Nishimura I, Wakamatsu K, Ito S, Takahashi R, Lu B: 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;102:13670-13675.
27.
Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A: DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2004;2:e362.
28.
Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL: The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol 2006;356:1036-1048.
29.
Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B: Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 2005;280:42655-42668.
30.
Zhang L, Shimoji M, Thomas B, Moore DJ, Yu S-W, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL: Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 2005;14:2063-2073.
31.
Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J: Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1. Neuron 2005;45:489-496.
32.
Zhong N, Kim CY, Rizzu P, Geula C, Porter DR, Pothos EN, Squitieri F, Heutink P, Xu J: DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor. J Biol Chem 2006;281:20940-20948.
33.
Zhou W, Freed CR: DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem 2005;280:43150-43158.
34.
Huang C, Cheng H, Hao S, Zhou H, Zhang X, Gao J, Sun QH, Hu H, Wang CC: Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. J Mol Biol 2006;364:323-336.
35.
Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ: Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 2004;279:25497-25502.
36.
Bové J, Perier C: Neurotoxin-based models of Parkinson's disease. Neuroscience 2012;211:51-76.
37.
Batelli S, Peverelli E, Rodilossi S, Forloni G, Albani D: Macroautophagy and the proteasome are differently involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model (PC12/TetOn). Neuroscience 2011;195:128-137.
38.
Kilic U, Kilic E, Dietz GPH, Bähr M: The TAT protein transduction domain enhances the neuroprotective effect of glial-cell-line-derived neurotrophic factor after optic nerve transection. Neurodegener Dis 2004;1:44-49.
39.
Albani D, Peverelli E, Rametta R, Batelli S, Veschini L, Negro A, Forloni G: Protective effect of TAT-delivered alpha-synuclein: relevance of the C-terminal domain and involvement of HSP70. FASEB J 2004;18:1713-1715.
40.
Peroni D, Negro A, Bähr M, Dietz GPH: Intracellular delivery of neuroglobin using HIV-1 TAT protein transduction domain fails to protect against oxygen and glucose deprivation. Neurosci Lett 2007;421:110-114.
41.
Forloni G, Bertani I, Calella AM, Thaler F, Invernizzi R: Alpha-synuclein and Parkinson's disease: selective neurodegenerative effect of alpha-synuclein fragment on dopaminergic neurons in vitro and in vivo. Ann Neurol 2000;47:632-640.
42.
Lasley SM, Michaelson IA, Greenland RD, McGinnis PM: Simultaneous measurement of tyrosine, tryptophan and related monoamines for determination of neurotransmitter turnover in discrete rat brain regions by liquid chromatography with electrochemical detection. J Chromatogr 1984;305:27-42.
43.
Taravini IR, Chertoff M, Cafferata EG, Courty J, Murer MG, Pitossi FJ, Gershanik OS: Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats. Mol Neurodegener 2011;6:40.
44.
Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ, Lee VM: Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012;338:949-953.
45.
Batelli S, Albani D, Rametta R, Polito L, Prato F, Pesaresi M, Negro A, Forloni G: DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson's disease and involvement of HSP70. PLoS One 2008;3:e1884.
46.
Lev N, Barhum Y, Ben-Zur T, Melamed E, Steiner I, Offen D: Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity. J Mol Neurosci 2013;50:542-550.
47.
Jeong HJ, Kim DW, Woo SJ, Kim HR, Kim SM, Jo HS, Park M, Kim DS, Kwon OS, Hwang IK, Han KH, Park J, Eum WS, Choi SY: Transduced Tat-DJ-1 protein protects against oxidative stress-induced SH-SY5Y cell death and Parkinson disease in a mouse model. Mol Cells 2012;33:471-478.
48.
Sun SY, An CN, Pu XP: DJ-1 protein protects dopaminergic neurons against 6-OHDA/MG-132-induced neurotoxicity in rats. Brain Res Bull 2012;88:609-616.
49.
Ramsey CP, Tsika E, Ischiropoulos H, Giasson BI: DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human alpha-syn toxicity. Hum Mol Genet 2010;19:1425-1437.
50.
Recchia A, Rota D, Debetto P, Peroni D, Guidolin D, Negro A, Skaper SD, Giusti P: Generation of an alpha-synuclein-based rat model of Parkinson's disease. Neurobiol Dis 2008;30:8-18.
51.
Moloney TC, Hyland R, O'Toole D, Paucard A, Kirik D, O'Doherty A, Gorman AM DE: Heat shock protein 70 reduces α-synuclein-induced predegenerative neuronal dystrophy in the α-synuclein viral gene transfer rat model of Parkinson's disease. CNS Neurosci Ther 2014;20:50-58.
52.
Auluck PK, Chan HYE, Trojanowski JQ, Lee VMY, Bonini NM: Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 2002;295:865-868.
53.
Liu F, Nguyen JL, Hulleman JD, Li L, Rochet JC: Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease. J Neurochem 2008;105:2435-2453.
54.
Ishikawa S, Taira T, Takahashi-Niki K, Niki T, Ariga H, Iguchi-Ariga SMM: Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene. J Biol Chem 2010;285:39718-39731.
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2014
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