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Value of genetic models in understanding the cause and mechanisms of Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the degeneration of nigrostriatal pathway dopaminergic neurons and other neuronal systems and the appearance of Lewy bodies that contain α-synuclein. PD is generally a sporadic disease, but a small proportion of cases have a clear genetic component. Mutations have been identified in six genes that clearly segregate with disease in rare families with PD. Transgenic, knockout, and virus-based models of disease have been developed in rodents to further understand how these genes contribute to the pathogenesis of PD. In general, these animal models recapitulate many key features of the disease, including derangements in dopaminergic synaptic transmission, selective neurodegeneration, neurochemical deficits, α-synuclein-positive neuropathology, and motor deficits. However, a genetic model with all or most of these pathogenic features has proved difficult to create. In this article, we discuss these mammalian genetic models of PD and what they have revealed about the cause and mechanisms of this disease.

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References and Recommended Reading

  1. Lang AE, Lozano AM: Parkinson’s disease. Second of two parts. N Engl J Med 1998, 339:1130–1143.

    Article  PubMed  CAS  Google Scholar 

  2. Lang AE, Lozano AM: Parkinson’s disease. First of two parts. N Engl J Med 1998, 339:1044–1053.

    Article  PubMed  CAS  Google Scholar 

  3. Gasser T: Genetics of Parkinson’s disease. Curr Opin Neurol 2005, 18:363–369.

    Article  PubMed  CAS  Google Scholar 

  4. Moore DJ, West AB, Dawson VL, Dawson TM: Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 2005, 28:57–87.

    Article  PubMed  CAS  Google Scholar 

  5. Meredith GE, Sonsalla PK, Chesselet MF: Animal models of Parkinson’s disease progression. Acta Neuropathol 2008, 115:385–398.

    Article  PubMed  Google Scholar 

  6. Whitworth AJ, Wes PD, Pallanck LJ: Drosophila models pioneer a new approach to drug discovery for Parkinson’s disease. Drug Discov Today 2006, 11:119–126.

    Article  PubMed  CAS  Google Scholar 

  7. Hamamichi S, Rivas RN, Knight AL, et al.: Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson’s disease model. Proc Natl Acad Sci U S A 2008, 105:728–733.

    Article  PubMed  CAS  Google Scholar 

  8. Cooper AA, Gitler AD, Cashikar A, et al.: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006, 313:324–328.

    Article  PubMed  CAS  Google Scholar 

  9. Fernagut PO, Chesselet MF: Alpha-synuclein and transgenic mouse models. Neurobiol Dis 2004, 17:123–130.

    Article  PubMed  CAS  Google Scholar 

  10. Giasson BI, Duda JE, Quinn SM, et al.: Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002, 34:521–533.

    Article  PubMed  CAS  Google Scholar 

  11. Lee MK, Stirling W, Xu Y, et al.: Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 right-arrow Thr mutation causes neurodegenerative disease with alpha-synclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 2002, 99:8968–8973.

    Article  PubMed  CAS  Google Scholar 

  12. van der Putten H, Wiederhold KH, Probst A, et al.: Neuropathology in mice expressing human alpha-synuclein. J Neurosci 2000, 20:6021–6029.

    PubMed  Google Scholar 

  13. Masliah E, Rockenstein E, Veinbergs I, et al.: Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000, 287:1265–1269.

    Article  PubMed  CAS  Google Scholar 

  14. Gomez-Isla T, Irizarry MC, Mariash A, et al.: Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 2003, 24:245–258.

    Article  PubMed  CAS  Google Scholar 

  15. Neumann M, Kahle PJ, Giasson BI, et al.: Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 2002, 110:1429–1439.

    PubMed  CAS  Google Scholar 

  16. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, et al.: Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 2002, 175:35–48.

    Article  PubMed  CAS  Google Scholar 

  17. Martin LJ, Pan Y, Price AC, et al.: Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 2006, 26:41–50.

    Article  PubMed  CAS  Google Scholar 

  18. Nuber S, Petrasch-Parwez E, Winner B, et al.: Neurodegeneration and motor dysfunction in a conditional model of Parkinson’s disease. J Neurosci 2008, 28:2471–2484.

    Article  PubMed  CAS  Google Scholar 

  19. Matsuoka Y, Vila M, Lincoln S, et al.: Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001, 8:535–539.

    Article  PubMed  CAS  Google Scholar 

  20. Li W, West N, Colla E, et al.: Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci U S A 2005, 102:2162–2167.

    Article  PubMed  CAS  Google Scholar 

  21. Liu CW, Giasson BI, Lewis KA, et al.: A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 2005, 280:22670–22678.

    Article  PubMed  CAS  Google Scholar 

  22. Crowther RA, Jakes R, Spillantini MG, Goedert M: Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett 1998, 436:309–312.

    Article  PubMed  CAS  Google Scholar 

  23. Murray IV, Giasson BI, Quinn SM, et al.: Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 2003, 42:8530–8540.

    Article  PubMed  CAS  Google Scholar 

  24. Tofaris GK, Garcia Reitbock P, Humby T, et al.: Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1–120): implications for Lewy body disorders. J Neurosci 2006, 26:3942–3950.

    Article  PubMed  CAS  Google Scholar 

  25. Wakamatsu M, Ishii A, Iwata S, et al.: Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice. Neurobiol Aging 2008, 29:574–585.

    Article  PubMed  CAS  Google Scholar 

  26. von Coelln R, Thomas B, Andrabi SA, et al.: Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J Neurosci 2006, 26:3685–3696.

    Article  Google Scholar 

  27. Ihara M, Yamasaki N, Hagiwara A, et al.: Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 2007, 53:519–533.

    Article  PubMed  CAS  Google Scholar 

  28. Gallardo G, Schluter OM, Sudhof TC: A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci 2008, 11:301–308.

    Article  PubMed  CAS  Google Scholar 

  29. Hashimoto M, Rockenstein E, Mante M, et al.: beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 2001, 32:213–223.

    Article  PubMed  CAS  Google Scholar 

  30. Fan Y, Limprasert P, Murray IV, et al.: Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression. Hum Mol Genet 2006, 15:3002–3011.

    Article  PubMed  CAS  Google Scholar 

  31. Klucken J, Shin Y, Masliah E, et al.: Hsp70 Reduces alpha-synuclein aggregation and toxicity. J Biol Chem 2004, 279:25497–25502.

    Article  PubMed  CAS  Google Scholar 

  32. Lo Bianco C, Ridet JL, Schneider BL, et al.: alpha-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci U S A 2002, 99:10813–10818.

    Article  PubMed  CAS  Google Scholar 

  33. Lo Bianco C, Schneider BL, Bauer M, et al.: Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004, 101:17510–17515.

    Article  PubMed  CAS  Google Scholar 

  34. Kirik D, Rosenblad C, Burger C, et al.: Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 2002, 22:2780–2791.

    PubMed  CAS  Google Scholar 

  35. Kirik D, Annett LE, Burger C, et al.: Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 2003, 100:2884–2889.

    Article  PubMed  CAS  Google Scholar 

  36. Von Coelln R, Thomas B, Savitt JM, et al.: Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A 2004, 101:10744–10749.

    Article  Google Scholar 

  37. Goldberg MS, Fleming SM, Palacino JJ, et al.: Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003, 278:43628–43635.

    Article  PubMed  CAS  Google Scholar 

  38. Itier JM, Ibanez P, Mena MA, et al.: Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 2003, 12:2277–2291.

    Article  PubMed  CAS  Google Scholar 

  39. Palacino JJ, Sagi D, Goldberg MS, et al.: Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004, 279:18614–18622.

    Article  PubMed  CAS  Google Scholar 

  40. Greene JC, Whitworth AJ, Kuo I, et al.: Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 2003, 100:4078–4083.

    Article  PubMed  CAS  Google Scholar 

  41. Thomas B, von Coelln R, Mandir AS, et al.: MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiol Dis 2007, 26:312–322.

    Article  PubMed  CAS  Google Scholar 

  42. Ko HS, Kim SW, Sriram SR, et al.: Identification of far upstream element-binding protein-1 as an authentic Parkin substrate. J Biol Chem 2006, 281:16193–16196.

    Article  PubMed  CAS  Google Scholar 

  43. Ko HS, von Coelln R, Sriram SR, et al.: Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J Neurosci 2005, 25:7968–7978.

    Article  PubMed  CAS  Google Scholar 

  44. Dong Z, Ferger B, Paterna JC, et al.: Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A 2003, 100:12438–12443.

    Article  PubMed  CAS  Google Scholar 

  45. Kitao Y, Imai Y, Ozawa K, et al.: Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. Hum Mol Genet 2007, 16:50–60.

    Article  PubMed  CAS  Google Scholar 

  46. Andres-Mateos E, Perier C, Zhang L, et al.: DJ-1 gene deletion reveals that DJ-1 is an atypical peroxire-doxin-like peroxidase. Proc Natl Acad Sci U S A 2007, 104:14807–14812.

    Article  PubMed  CAS  Google Scholar 

  47. Chen L, Cagniard B, Mathews T, et al.: Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 2005, 280:21418–21426.

    Article  PubMed  CAS  Google Scholar 

  48. Goldberg MS, Pisani A, Haburcak M, et al.: Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 2005, 45:489–496.

    Article  PubMed  CAS  Google Scholar 

  49. Manning-Bog AB, Caudle WM, Perez XA, et al.: Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. Neurobiol Dis 2007, 27:141–150.

    Article  PubMed  CAS  Google Scholar 

  50. Kim RH, Smith PD, Aleyasin H, et al.: 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, 102:5215–5220.

    Article  PubMed  CAS  Google Scholar 

  51. Zhang L, Shimoji M, Thomas B, et al.: Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 2005, 14:2063–2073.

    Article  PubMed  CAS  Google Scholar 

  52. Moore DJ, Dawson VL, Dawson TM: Lessons from Drosophila models of DJ-1 deficiency. Sci Aging Knowledge Environ 2006, 2006:pe2.

    Article  PubMed  Google Scholar 

  53. Kitada T, Pisani A, Porter DR, et al.: Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A 2007, 104:11441–11446.

    Article  PubMed  CAS  Google Scholar 

  54. Clark IE, Dodson MW, Jiang C, et al.: Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006, 441:1162–1166.

    Article  PubMed  CAS  Google Scholar 

  55. Park J, Lee SB, Lee S, et al.: Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006, 441:1157–1161.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Darren J. Moore.

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Moore, D.J., Dawson, T.M. Value of genetic models in understanding the cause and mechanisms of Parkinson’s disease. Curr Neurol Neurosci Rep 8, 288–296 (2008). https://doi.org/10.1007/s11910-008-0045-7

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