Home LiteratureArticle Details
PMID: 20547124 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Genetic animal models of Parkinson's disease.

Neuron ·Vol. 66 ·No. 5 ·2010-06-10 ·Pages 646-61

Dawson TM, Ko HS, Dawson VL

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the degeneration of dopamine (DA) and non-DA neurons, the almost uniform presence of Lewy bodies, and motor deficits. Although the majority of PD is sporadic, specific genetic defects in rare familial cases have provided unique insights into the pathogenesis of PD. Through the creation of animal and cellular models of mutations in LRRK2 and alpha-synuclein, which are linked to autosomal-dominant PD, and mutations in parkin, DJ-1, and PINK1, which are responsible for autosomal-recessive PD, insight into the molecular mechanisms of this disorder are leading to new ideas about the pathogenesis of PD. In this review, we discuss the animal models for these genetic causes of PD, their limitations, and value. Moreover, we discuss future directions and potential strategies for optimization of the genetic models.

MeSH Terms
Animals Cell Death/genetics Disease Models, Animal Humans Mice Mice, Transgenic Neurodegenerative Diseases/genetics,pathology,therapy Parkinson Disease/genetics,pathology,therapy
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dawson Ted M
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu
Ko Han Seok
Dawson Valina L
References (160)
160 references, click to expand
  1. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain.
    J Biol Chem. 2008 Apr 4;283(14):9089-100 PMID: 18245082
  2. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy.
    Science. 2004 Aug 27;305(5688):1292-5 PMID: 15333840
  3. A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine.
    J Neurosci. 2007 Jan 31;27(5):981-92 PMID: 17267552
  4. Loss of locus coeruleus neurons and reduced startle in parkin null mice.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10744-9 PMID: 15249681
  5. Renal and neuronal abnormalities in mice lacking GDNF.
    Nature. 1996 Jul 4;382(6586):76-9 PMID: 8657308
  6. Is malfunction of the ubiquitin proteasome system the primary cause of alpha-synucleinopathies and other chronic human neurodegenerative disease?
    Biochim Biophys Acta. 2008 Dec;1782(12):683-90 PMID: 18976704
  7. RET is dispensable for maintenance of midbrain dopaminergic neurons in adult mice.
    J Neurosci. 2006 Oct 25;26(43):11230-8 PMID: 17065462
  8. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice.
    Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73 PMID: 12084935
  9. The role of parkin in familial and sporadic Parkinson's disease.
    Mov Disord. 2010;25 Suppl 1:S32-9 PMID: 20187240
  10. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila.
    Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8 PMID: 18799731
  11. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.
    Science. 2003 Jan 10;299(5604):256-9 PMID: 12446870
  12. DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human alpha-syn toxicity.
    Hum Mol Genet. 2010 Apr 15;19(8):1425-37 PMID: 20089532
  13. Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death.
    J Neurosci. 2006 Jan 4;26(1):41-50 PMID: 16399671
  14. LRRK2 mutations and Parkinsonism.
    Lancet. 2005 Apr 2-8;365(9466):1230 PMID: 15811455
  15. Molecular pathways of neurodegeneration in Parkinson's disease.
    Science. 2003 Oct 31;302(5646):819-22 PMID: 14593166
  16. alpha-Synuclein locus triplication causes Parkinson's disease.
    Science. 2003 Oct 31;302(5646):841 PMID: 14593171
  17. The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2.
    J Neurosci. 2008 Mar 26;28(13):3384-91 PMID: 18367605
  18. 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 Apr 5;102(14):5215-20 PMID: 15784737
  19. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.
    Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5 PMID: 19651612
  20. Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress.
    Curr Biol. 2005 Sep 6;15(17):1578-82 PMID: 16139214
  21. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice.
    J Neurochem. 2009 Nov;111(3):696-702 PMID: 19694908
  22. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
    Cell. 2005 Nov 4;123(3):383-96 PMID: 16269331
  23. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1.
    Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9 PMID: 11078524
  24. Genetic models of Parkinson disease.
    Biochim Biophys Acta. 2009 Jul;1792(7):604-15 PMID: 19000757
  25. Abnormal colonic motility in mice overexpressing human wild-type alpha-synuclein.
    Neuroreport. 2008 May 28;19(8):873-6 PMID: 18463504
  26. Mice lacking alpha-synuclein are resistant to mitochondrial toxins.
    Neurobiol Dis. 2006 Mar;21(3):541-8 PMID: 16298531
  27. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.
    Science. 2004 May 28;304(5675):1328-31 PMID: 15105460
  28. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):8024-9 PMID: 15911761
  29. The biochemistry of Parkinson's disease.
    Annu Rev Biochem. 2005;74:29-52 PMID: 15952880
  30. Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons.
    Mol Neurodegener. 2009 Jul 24;4:34 PMID: 19630976
  31. DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase.
    Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14807-12 PMID: 17766438
  32. alpha-Synuclein and Parkinson disease susceptibility.
    Neurology. 2007 Oct 30;69(18):1745-50 PMID: 17872362
  33. The Parkinson's complex: parkinsonism is just the tip of the iceberg.
    Ann Neurol. 2006 Apr;59(4):591-6 PMID: 16566021
  34. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice.
    Exp Neurol. 2002 May;175(1):35-48 PMID: 12009758
  35. 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 Aug 6;99(16):10813-8 PMID: 12122208
  36. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S.
    J Neurosci. 2010 Feb 3;30(5):1788-97 PMID: 20130188
  37. Non-autonomous cell death in Parkinson's disease.
    Lancet Neurol. 2008 Jun;7(6):474-5 PMID: 18485311
  38. Mitochondria in the aetiology and pathogenesis of Parkinson's disease.
    Lancet Neurol. 2008 Jan;7(1):97-109 PMID: 18093566
  39. Strengths and limitations of genetic mouse models of Parkinson's disease.
    Parkinsonism Relat Disord. 2008;14 Suppl 2:S84-7 PMID: 18585084
  40. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.
    PLoS One. 2009 Jun 03;4(6):e5777 PMID: 19492057
  41. Toxin-induced models of Parkinson's disease.
    NeuroRx. 2005 Jul;2(3):484-94 PMID: 16389312
  42. Absolute requirement of GDNF for adult catecholaminergic neuron survival.
    Nat Neurosci. 2008 Jul;11(7):755-61 PMID: 18536709
  43. Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP.
    Exp Neurol. 2004 Apr;186(2):158-72 PMID: 15026254
  44. The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):145-50 PMID: 18162536
  45. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.
    J Neurosci. 2008 Mar 5;28(10):2471-84 PMID: 18322092
  46. A Drosophila model for LRRK2-linked parkinsonism.
    Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2693-8 PMID: 18258746
  47. Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin.
    Trends Neurosci. 2005 Aug;28(8):416-21 PMID: 15955578
  48. The PINK1/Parkin pathway regulates mitochondrial morphology.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43 PMID: 18230723
  49. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease.
    Nat Neurosci. 2005 May;8(5):657-63 PMID: 15834418
  50. Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
    Ann Neurol. 2006 Nov;60(5):557-69 PMID: 17120249
  51. Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction.
    Gene. 2005 Nov 21;361:133-9 PMID: 16203113
  52. 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 Sep 20;102(38):13670-5 PMID: 16155123
  53. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease.
    Nat Neurosci. 2009 Jul;12(7):826-8 PMID: 19503083
  54. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
    Science. 1994 Jun 17;264(5166):1772-5 PMID: 8209258
  55. Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities.
    J Neurosci. 2007 Aug 8;27(32):8563-70 PMID: 17687034
  56. Kinase activity of mutant LRRK2 mediates neuronal toxicity.
    Nat Neurosci. 2006 Oct;9(10):1231-3 PMID: 16980962
  57. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.
    Neuron. 2004 Nov 18;44(4):595-600 PMID: 15541308
  58. Nosology of Parkinson's disease: looking for the way out of a quagmire.
    Neuron. 2005 Aug 18;47(4):479-82 PMID: 16102530
  59. Neuropathology in mice expressing human alpha-synuclein.
    J Neurosci. 2000 Aug 15;20(16):6021-9 PMID: 10934251
  60. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1.
    Neuron. 2005 Feb 17;45(4):489-96 PMID: 15721235
  61. Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice.
    Eur J Neurosci. 2004 Feb;19(4):845-54 PMID: 15009131
  62. Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis.
    Biochim Biophys Acta. 2009 Jul;1792(7):651-63 PMID: 19059336
  63. The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
    Neuron. 2006 Nov 22;52(4):587-93 PMID: 17114044
  64. LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans.
    J Neurosci. 2009 Jul 22;29(29):9210-8 PMID: 19625511
  65. Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease.
    Biochim Biophys Acta. 2009 Jul;1792(7):625-33 PMID: 18973807
  66. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.
    Hum Mol Genet. 2005 Nov 15;14(22):3477-92 PMID: 16207731
  67. Alpha-synuclein and neurodegenerative diseases.
    Nat Rev Neurosci. 2001 Jul;2(7):492-501 PMID: 11433374
  68. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.
    Nat Genet. 2006 Oct;38(10):1184-91 PMID: 16964263
  69. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress.
    Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11364-9 PMID: 18687901
  70. Olfactory deficits in mice overexpressing human wildtype alpha-synuclein.
    Eur J Neurosci. 2008 Jul;28(2):247-56 PMID: 18702696
  71. Presymptomatic compensation in Parkinson's disease is not dopamine-mediated.
    Trends Neurosci. 2003 Apr;26(4):215-21 PMID: 12689773
  72. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.
    J Biol Chem. 2004 Apr 30;279(18):18614-22 PMID: 14985362
  73. Diagnosis and treatment of Parkinson disease: molecules to medicine.
    J Clin Invest. 2006 Jul;116(7):1744-54 PMID: 16823471
  74. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.
    Neuron. 2000 Jan;25(1):239-52 PMID: 10707987
  75. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.
    Hum Mol Genet. 2003 Sep 15;12(18):2277-91 PMID: 12915482
  76. DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders.
    Free Radic Biol Med. 2009 Nov 15;47(10):1354-61 PMID: 19686841
  77. Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.
    Hum Mol Genet. 2009 Nov 15;18(22):4390-404 PMID: 19692353
  78. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.
    Science. 2006 Jul 21;313(5785):324-8 PMID: 16794039
  79. Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus.
    Brain Res. 1999 May 15;828(1-2):91-103 PMID: 10320728
  80. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death.
    Mol Cell. 2009 Mar 13;33(5):627-38 PMID: 19285945
  81. Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
    J Neurosci. 2009 Dec 16;29(50):15846-50 PMID: 20016100
  82. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.
    Nature. 2006 Jun 29;441(7097):1162-6 PMID: 16672981
  83. MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity.
    Neurobiol Dis. 2007 May;26(2):312-22 PMID: 17336077
  84. Alpha-synuclein dysfunction in Lewy body diseases.
    Mov Disord. 2005 Aug;20 Suppl 12:S37-44 PMID: 16092089
  85. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
    Neuron. 2004 Nov 18;44(4):601-7 PMID: 15541309
  86. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis.
    Hum Mol Genet. 2005 Jul 15;14(14):2063-73 PMID: 15944198
  87. The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes.
    Hum Mol Genet. 2003 Nov 1;12(21):2807-16 PMID: 12952867
  88. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein.
    Neuron. 2002 May 16;34(4):521-33 PMID: 12062037
  89. Association between early-onset Parkinson's disease and mutations in the parkin gene.
    N Engl J Med. 2000 May 25;342(21):1560-7 PMID: 10824074
  90. Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila.
    J Neurosci. 2009 Sep 9;29(36):11257-62 PMID: 19741132
  91. Alpha-synuclein pathology and Parkinsonism associated with POLG1 mutations and multiple mitochondrial DNA deletions.
    Neuropathol Appl Neurobiol. 2009 Feb;35(1):120-4 PMID: 19187065
  92. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
    Nature. 2006 Jun 29;441(7097):1157-61 PMID: 16672980
  93. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.
    Neuron. 2010 Jan 14;65(1):66-79 PMID: 20152114
  94. In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson's disease?
    Exp Neurol. 2008 Jan;209(1):22-7 PMID: 17949715
  95. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.
    Nat Med. 2008 May;14(5):501-3 PMID: 18391963
  96. A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders.
    Biochim Biophys Acta. 2009 Jul;1792(7):730-40 PMID: 18718530
  97. Lessons from Drosophila models of DJ-1 deficiency.
    Sci Aging Knowledge Environ. 2006 Jan 11;2006(2):pe2 PMID: 16407572
  98. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein.
    J Neurochem. 2003 Jul;86(1):165-72 PMID: 12807436
  99. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions.
    Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14966-71 PMID: 15465911
  100. Autophagy and neurodegeneration.
    Autophagy. 2006 Oct-Dec;2(4):315-7 PMID: 16874063
  101. Whole-mount analysis reveals normal numbers of dopaminergic neurons following misexpression of alpha-Synuclein in Drosophila.
    Genesis. 2005 Apr;41(4):154-9 PMID: 15789427
  102. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters.
    J Neurosci Res. 2002 Jun 1;68(5):568-78 PMID: 12111846
  103. A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization.
    J Neurochem. 2003 Dec;87(6):1558-67 PMID: 14713311
  104. The kinase domain of mitochondrial PINK1 faces the cytoplasm.
    Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12022-7 PMID: 18687899
  105. Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice.
    Neurobiol Aging. 2007 Sep;28(9):1421-35 PMID: 16872721
  106. Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10810-4 PMID: 15252205
  107. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
    PLoS Biol. 2010 Jan 26;8(1):e1000298 PMID: 20126261
  108. R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice.
    Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7 PMID: 19667187
  109. Parkin-deficient mice are not a robust model of parkinsonism.
    Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2174-9 PMID: 15684050
  110. Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo.
    J Neurosci. 2007 Mar 21;27(12):3338-46 PMID: 17376994
  111. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila.
    EMBO J. 2008 Sep 17;27(18):2432-43 PMID: 18701920
  112. Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered.
    Mov Disord. 2006 Dec;21(12):2042-51 PMID: 17078043
  113. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
    Nature. 1998 Apr 9;392(6676):605-8 PMID: 9560156
  114. 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 Feb 8;102(6):2162-7 PMID: 15684072
  115. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83 PMID: 12642658
  116. Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans.
    J Biol Chem. 2006 Jan 6;281(1):334-40 PMID: 16260788
  117. Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice.
    Neurobiol Aging. 2008 Apr;29(4):574-85 PMID: 17174013
  118. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.
    Neuron. 2009 Dec 24;64(6):807-27 PMID: 20064389
  119. Lrrk2 and Lewy body disease.
    Ann Neurol. 2006 Feb;59(2):388-93 PMID: 16437559
  120. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
    Hum Mol Genet. 2007 Jan 15;16(2):223-32 PMID: 17200152
  121. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study.
    Lancet Neurol. 2008 Jul;7(7):583-90 PMID: 18539534
  122. PINK-1 and DJ-1--new genes for autosomal recessive Parkinson's disease.
    J Neural Transm Suppl. 2006;(70):215-9 PMID: 17017532
  123. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.
    Nat Med. 2008 May;14(5):504-6 PMID: 18391962
  124. Hereditary early-onset Parkinson's disease caused by mutations in PINK1.
    Science. 2004 May 21;304(5674):1158-60 PMID: 15087508
  125. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein.
    J Neurosci. 2009 Feb 18;29(7):1962-76 PMID: 19228951
  126. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1716-21 PMID: 18218782
  127. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice.
    Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11441-6 PMID: 17563363
  128. LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins.
    Curr Biol. 2007 Apr 3;17(7):592-8 PMID: 17346966
  129. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons.
    Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30 PMID: 17227870
  130. Association of glucocerebrosidase mutations with dementia with lewy bodies.
    Arch Neurol. 2009 May;66(5):578-83 PMID: 19433657
  131. Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery.
    Neuron. 2006 Oct 5;52(1):33-8 PMID: 17015225
  132. Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons.
    Mol Neurodegener. 2008 Feb 08;3:3 PMID: 18257932
  133. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.
    Nat Med. 1998 Nov;4(11):1318-20 PMID: 9809558
  134. Molecular pathophysiology of Parkinson's disease.
    Annu Rev Neurosci. 2005;28:57-87 PMID: 16022590
  135. What causes cell death in Parkinson's disease?
    Ann Neurol. 2008 Dec;64 Suppl 2:S3-15 PMID: 19127586
  136. Dopamine covalently modifies and functionally inactivates parkin.
    Nat Med. 2005 Nov;11(11):1214-21 PMID: 16227987
  137. 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 Mar 4;100(5):2884-9 PMID: 12601150
  138. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin.
    Neurobiol Dis. 2006 Aug;23(2):329-41 PMID: 16750377
  139. Parkinson's disease: mechanisms and models.
    Neuron. 2003 Sep 11;39(6):889-909 PMID: 12971891
  140. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways.
    Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10244-9 PMID: 18626009
  141. Parkinson's disease.
    Lancet. 2009 Jun 13;373(9680):2055-66 PMID: 19524782
  142. Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model.
    Am J Pathol. 2007 Feb;170(2):658-66 PMID: 17255333
  143. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery.
    Proc Natl Acad Sci U S A. 2008 May 13;105(19):7070-5 PMID: 18443288
  144. Parkin is linked to the ubiquitin pathway.
    J Mol Med (Berl). 2001 Sep;79(9):482-94 PMID: 11692161
  145. Functional and molecular differentiation of the dopamine system induced by neonatal denervation.
    Neurosci Biobehav Rev. 1996 Autumn;20(3):453-86 PMID: 8880735
  146. Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila.
    Biochem Biophys Res Commun. 2007 Jun 29;358(2):534-9 PMID: 17498648
  147. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
    Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83 PMID: 19966284
  148. Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies.
    J Clin Invest. 2002 Nov;110(10):1429-39 PMID: 12438441
  149. Amyloid precursor protein transgenic mouse models and Alzheimer's disease: understanding the paradigms, limitations, and contributions.
    Alzheimers Dement. 2009 Jul;5(4):340-7 PMID: 19560104
  150. A network dysfunction perspective on neurodegenerative diseases.
    Nature. 2006 Oct 19;443(7113):768-73 PMID: 17051202
  151. Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.
    Neurobiol Dis. 2001 Jun;8(3):535-9 PMID: 11442360
  152. Animal models of PD: pieces of the same puzzle?
    Neuron. 2002 Jul 18;35(2):219-22 PMID: 12160740
  153. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years.
    Nat Med. 2008 May;14(5):507-9 PMID: 18391961
  154. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease.
    Nat Med. 1999 Dec;5(12):1403-9 PMID: 10581083
  155. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase.
    Nat Genet. 2000 Jul;25(3):302-5 PMID: 10888878
  156. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy.
    J Neurosci. 2006 Apr 5;26(14):3685-96 PMID: 16597723
  157. Do polymorphisms in the familial Parkinsonism genes contribute to risk for sporadic Parkinson's disease?
    Mov Disord. 2009 Apr 30;24(6):833-8 PMID: 19224617
  158. A Drosophila model of Parkinson's disease.
    Nature. 2000 Mar 23;404(6776):394-8 PMID: 10746727
  159. Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease.
    Curr Biol. 2005 Sep 6;15(17):1572-7 PMID: 16139213
  160. Molecular pathogenesis of Parkinson disease: insights from genetic studies.
    Expert Rev Mol Med. 2009 Jul 27;11:e22 PMID: 19631006
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2010.04.034
Email
tdawson@jhmi.edu
Published
2010-06-10
Pages
646-61
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2917798
Subset
IM
Grants
NINDS NIH HHS · R01 NS048206-05S1 · United States
NINDS NIH HHS · NS04826 · United States
NINDS NIH HHS · P50 NS038377-10S2 · United States
NINDS NIH HHS · NS38377 · United States
NINDS NIH HHS · P50 NS038377-109001 · United States
NINDS NIH HHS · P50 NS038377-11 · United States
NINDS NIH HHS · P50 NS038377-10S1 · United States
NINDS NIH HHS · R01 NS048206 · United States
NINDS NIH HHS · P50 NS038377-115295 · United States
NINDS NIH HHS · P50 NS038377 · United States
NINDS NIH HHS · P50 NS038377-115290 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2010.04.034 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2