Dissecting the Biochemical Pathways Mediated by Genes Implicated in Parkinson’s Disease: Induction of DJ-1 Expression in A30P α-Synuclein Mice

  • Mark Frasier
  • Shanti Frausto
  • Daniel Lewicki
  • Lawrence Golbe
  • Benjamin Wolozin
Part of the Advances in Behavioral Biology book series (ABBI, volume 57)


Multiple System Atrophy Lewy Body Nontransgenic Mouse Symptomatic Animal Symptomatic Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3(12):1301–1306PubMedCrossRefGoogle Scholar
  2. 2.
    Thiruchelvam M, Richfield EK, Bagg, RB, et al. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J Neurosci 2000;20(24):9207–9214PubMedGoogle Scholar
  3. 3.
    Manning-Bog AB, McCormack AL, Li J, et al. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 2002;277(3):1641–1644PubMedCrossRefGoogle Scholar
  4. 4.
    Engel LS, Checkoway H, Keifer MC, et al. Parkinsonism and occupational exposure to pesticides. Occup Environ Med 2001;58(9):582–589PubMedCrossRefGoogle Scholar
  5. 5.
    Gorell J, Rybicki B, Cole-Johnson C, Peterson E. Occupational metal exposures and the risk of Parkinson's disease. Neuroepidemiology 1999;18:303–308PubMedCrossRefGoogle Scholar
  6. 6.
    Liou HH, Tsai MC, Chen CJ, et al. Environmental risk factors and Parkinson's disease: a case-control study in Taiwan. Neurology 1997;48(6):1583–1588PubMedGoogle Scholar
  7. 7.
    Golbe LI, Farrell TM, Davis PH. Case-control study of early life dietary factors in Parkinson's disease. Arch Neurol 1988;45(12):1350–1353PubMedGoogle Scholar
  8. 8.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276(5321):2045–2047PubMedCrossRefGoogle Scholar
  9. 9.
    Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat Gen 1998;18:106–108CrossRefGoogle Scholar
  10. 10.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes parkinson and Lewy body dementia. Ann Neurol 2004;55(2):164–173PubMedCrossRefGoogle Scholar
  11. 11.
    Kitada T, Asakawa S, Hattori, N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605–608PubMedCrossRefGoogle Scholar
  12. 12.
    Bonifati, V, Rizzu, P, Squitieri, F, et al. DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 2003;24(3):159–160PubMedCrossRefGoogle Scholar
  13. 13.
    Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;304(5674):1158–1160PubMedCrossRefGoogle Scholar
  14. 14.
    Singleton AB, Farrer M, Johnson J, et al. α-Synuclein locus triplication causes Parkinson's disease. Science 2003;302(5646):841PubMedCrossRefGoogle Scholar
  15. 15.
    Hashimoto M, Takeda A, Hsu L, et al. Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J Biol Chem 1999;274:28849–8852PubMedCrossRefGoogle Scholar
  16. 16.
    Paik S, Shin H, Lee J, et al. Copper(II)-induced self-oligomerization of α-synuclein. Biochem J 1999;340:821–828PubMedCrossRefGoogle Scholar
  17. 17.
    Paik SR, Shin HJ, Lee JH. Metal-catalyzed oxidation of alpha-synuclein in the presence of copper(II) and hydrogen peroxide. Arch Biochem Biophys 2000;378(2):269–277PubMedCrossRefGoogle Scholar
  18. 18.
    Ostrerova-Golts N, Petrucelli L, Hardy J, et al. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 2000;20:6048–6054PubMedGoogle Scholar
  19. 19.
    Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000;287(5456):1265–1269PubMedCrossRefGoogle Scholar
  20. 20.
    Giasson BI, Duda J, Quinn SM., et al. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002;34(4):521–533PubMedCrossRefGoogle Scholar
  21. 21.
    Lee M, Stirling W, Xu Y, et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 to Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 2002;99:8968–8973PubMedCrossRefGoogle Scholar
  22. 22.
    Kahle PJ, Neumann M, Ozmen L, et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J Neurosci 2000;20(17):6365–6373PubMedGoogle Scholar
  23. 23.
    Kahle PJ, Neumann M, Ozmen L, et al. Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001;159(6):2215–2225PubMedGoogle Scholar
  24. 24.
    Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305(5688):1292–1295PubMedCrossRefGoogle Scholar
  25. 25.
    Murphy DD, Rueter SM, Trojanowski, JQ, Lee VM. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000;20(9):3214–3220PubMedGoogle Scholar
  26. 26.
    Sharon R, Goldberg MS, Bar-Josef I, et al. α-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc Natl Acad Sci U S A 2001;98(16):9110–9115PubMedCrossRefGoogle Scholar
  27. 27.
    Perrin RJ, Woods WS, Clayton DF, George JM. Interaction of human α-synuclein and Parkinson's disease variants with phospholipids: structural analysis using site-directed mutagenesis. J Biol Chem 2000;275:34393–34398PubMedCrossRefGoogle Scholar
  28. 28.
    Perrin RJ, Woods WS, Clayton DF, George JM. Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 2001;276(45): 41958–41962PubMedCrossRefGoogle Scholar
  29. 29.
    Ostrerova N, Petrucelli L, Farrer M, et al. α-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 1999;19:5782–5791PubMedGoogle Scholar
  30. 30.
    Xu J, Kao S, Lee F, et al. Dopamine-dependent neurotoxicity in α-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 2002;5:600–606CrossRefGoogle Scholar
  31. 31.
    Souza, JM, Giasson BI, Lee VM, Ischiropoulos H. Chaperone-like activity of synucleins. FEBS Lett 2000;474(1):116–119PubMedCrossRefGoogle Scholar
  32. 32.
    Jenco J, Rawlingson A, Daniels B, Morris A. Regulation of phospholipase D2: Selective inhibition of mammalian phospholipase D isoenzymes by α and β synucleins. Biochemistry 1998;37:4901–4909PubMedCrossRefGoogle Scholar
  33. 33.
    Engelender S, Kaminsky Z, Guo X, et al. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 1999;22:110–114PubMedCrossRefGoogle Scholar
  34. 34.
    Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem 2000;275:26515–26522PubMedCrossRefGoogle Scholar
  35. 35.
    Choi P, Snyder H, Petrucelli L, et al. SEPT5_v2 is a parkin-binding protein. Brain Res Mol Brain Res 2003;117(2):179–189PubMedCrossRefGoogle Scholar
  36. 36.
    Lee FJ, Liu F, Pristupa ZB, Niznik HB. Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J 2001;15(6):916–926PubMedCrossRefGoogle Scholar
  37. 37.
    Ihara M, Tomimoto H, Kitayama H, et al. Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies. J Biol Chem 2003;278(26):24095–24102PubMedCrossRefGoogle Scholar
  38. 38.
    Snyder H, Mensah K, Theisler C, et al. Aggregated and monomeric alpha-synuclein bind to the S6' proteasomal protein and inhibit proteasomal function. J Biol Chem 2003;278(14):11753–11759PubMedCrossRefGoogle Scholar
  39. 39.
    Lindersson E, Beedholm R, Hojrup P, et al. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 2004;279(13):12924–12934PubMedCrossRefGoogle Scholar
  40. 40.
    Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604):256–259PubMedCrossRefGoogle Scholar
  41. 41.
    Honbou K, Suzuki NN, Horiuchi M, et al. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J Biol Chem 2003;278(33):31380–31384PubMedCrossRefGoogle Scholar
  42. 42.
    Tao X, Tong L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease. J Biol Chem 2003;278:(33)31372–31379PubMedCrossRefGoogle Scholar
  43. 43.
    Moore DJ, Dawson VL, Dawson TM. Genetics of Parkinson's disease: What do mutations in DJ-1 tell us? Ann Neurol 2003;54(3):281–282PubMedCrossRefGoogle Scholar
  44. 44.
    Bandopadhyay R, Kingsbury AE, et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain 2004;127(Pt 2):420–430PubMedCrossRefGoogle Scholar
  45. 45.
    Shendelman S, Jonason A, Martinat C, et al. DJ-1 is a redox-dependent molecular chaperone that inhibits α-synuclein aggregate formation. PLoS Biol 2004;2:e362PubMedCrossRefGoogle Scholar
  46. 46.
    Yokota T, Sugawara K, Ito K, et al. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 2003;312(4):1342–1348PubMedCrossRefGoogle Scholar
  47. 47.
    Martinat C, Shendelman S, Jonason A, et al. Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: and ES-derived cell model of primary parkinsonism. PLoS Biol 2004;2:e327PubMedCrossRefGoogle Scholar
  48. 48.
    Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 2004;101(24):9103–9108PubMedCrossRefGoogle Scholar
  49. 49.
    Duda JE, Giasson BI, Mabon ME, et al. Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol (Berl) 2002;104(1):7–11CrossRefGoogle Scholar
  50. 50.
    Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003;300(5619):636–640PubMedCrossRefGoogle Scholar
  51. 51.
    Frasier M, Walzer M, McCarthy L, et al. Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 2005;192(2):274–287PubMedCrossRefGoogle Scholar
  52. 52.
    Rizzu P, Hinkle DA, Zhukareva V, et al. DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia. Ann Neurol 2004;55(1):113–118PubMedCrossRefGoogle Scholar
  53. 53.
    Neumann M, Muller V, Gorner K, et al. Pathological properties of the Parkinson's disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick's disease. Acta Neuropathol (Berl) 2004;107(6): 489–496CrossRefGoogle Scholar
  54. 54.
    Sahara N, Lewis J, DeTure M, et al. Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility. J Neurochem 2002;83(6): 1498–1508PubMedCrossRefGoogle Scholar
  55. 55.
    Olzmann JA, Brown K, Wilkinson KD, et al. Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function. J Biol Chem 2004;279(9):8506–8515PubMedCrossRefGoogle Scholar
  56. 56.
    Wang JZ, Wu Q, Smith A, et al. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett 1998;436(1):28–34PubMedCrossRefGoogle Scholar
  57. 57.
    Biernat J, Mandelkow EM, Schroter C, et al. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J 1992;11(4):1593–1597PubMedGoogle Scholar
  58. 58.
    Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron 2003;39(6):889–909PubMedCrossRefGoogle Scholar
  59. 59.
    Sherer TB, Betarbet R, Testa CM, et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci 2003;23(34):10756–10764PubMedGoogle Scholar
  60. 60.
    Jensen PH, Hager H, Nielsen MS, et al. Alpha-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 1999;274(36):25481–25489PubMedCrossRefGoogle Scholar
  61. 61.
    Forman MS, Schmidt ML, Kasturi S, et al. Tau and alpha-synuclein pathology in amygdala of parkinsonism-dementia complex patients of Guam. Am J Pathol 2002;160(5):1725–1731PubMedGoogle Scholar
  62. 62.
    Ishizawa T, Mattila P, Davies P, et al. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 2004;62(4):389–397Google Scholar
  63. 63.
    Bandyopadhyay S, Cookson MR. Evolutionary and functional relationships within the DJ1 superfamily. BMC Evol Biol 2004;4(1):6PubMedCrossRefGoogle Scholar
  64. 64.
    Petrucelli L, Dickson D, Kehoe K, et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 2004;13(7):703–714PubMedCrossRefGoogle Scholar
  65. 65.
    Shimura H, Schwartz D, Gygi SP, Kosik KS. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 2004;279(6):4869–4876PubMedCrossRefGoogle Scholar
  66. 66.
    Imai Y, Soda M, Hatakeyama S, et al. CHIP is associated with parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell 2002;10(1):55–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mark Frasier
    • 1
  • Shanti Frausto
  • Daniel Lewicki
  • Lawrence Golbe
  • Benjamin Wolozin
  1. 1.Michael J. Fox FoundationNewYorkUSA

Personalised recommendations