Home LiteratureArticle Details
PMID: 21249202 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice.

PloS one ·Vol. 6 ·No. 1 ·2011-01-13 ·Pages e16038

Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, Sullivan PG, Büeler H

Abstract

PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca²+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1⁻/⁻ mice. Purified brain mitochondria of Pink1⁻/⁻ mice showed impaired Ca²+ storage capacity, resulting in increased Ca²+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1⁻/⁻ mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1⁻/⁻ mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1⁻/⁻ mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1⁻/⁻ embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1⁻/⁻ mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. Increased mitochondrial Ca²+ sensitivity and JNK activity are early defects in Pink1⁻/⁻ mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1⁻/⁻ mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1⁻/⁻ mice to inflammation and injury-induced cell death.

MeSH Terms
Animals Brain/metabolism,ultrastructure Calcium/metabolism Corpus Striatum Dopamine/deficiency Gene Expression Regulation Immunity, Innate/genetics Inflammation/etiology JNK Mitogen-Activated Protein Kinases/metabolism Mice Mice, Knockout Mitochondria/metabolism Mitochondrial Membrane Transport Proteins Mitochondrial Permeability Transition Pore NF-kappa B/metabolism Neurons/pathology Parkinson Disease/genetics,immunology,pathology Protein Kinases/deficiency,metabolism
Chemicals
Mitochondrial Membrane Transport Proteins Mitochondrial Permeability Transition Pore NF-kappa B Protein Kinases PTEN-induced putative kinase JNK Mitogen-Activated Protein Kinases Calcium Dopamine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Akundi Ravi S
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
Huang Zhenyu
Eason Joshua
Pandya Jignesh D
Zhi Lianteng
Cass Wayne A
Sullivan Patrick G
Büeler Hansruedi
References (143)
143 references, click to expand
  1. Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats.
    J Neurochem. 2010 Feb;112(3):773-83 PMID: 19922440
  2. Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration.
    J Neurosci Res. 1997 Sep 15;49(6):681-97 PMID: 9335256
  3. MAPK phosphatases--regulating the immune response.
    Nat Rev Immunol. 2007 Mar;7(3):202-12 PMID: 17318231
  4. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation.
    Nature. 2000 Jul 6;406(6791):86-90 PMID: 10894547
  5. Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum.
    Eur J Neurosci. 1996 Feb;8(2):365-81 PMID: 8714707
  6. Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: Two approaches with therapeutic potential in the treatment of neurodegenerative disease.
    Pharmacol Ther. 2007 Jun;114(3):261-77 PMID: 17399794
  7. Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease.
    Mol Ther. 2005 Jan;11(1):80-8 PMID: 15585408
  8. Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation.
    Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1109-14 PMID: 18650318
  9. D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons.
    Neuroscience. 1992 Jul;49(2):285-96 PMID: 1359451
  10. Amphiregulin acts as an autocrine survival factor for adult sensory neurons.
    Neuroreport. 2005 Feb 28;16(3):213-8 PMID: 15706222
  11. Linking oxidative stress to inflammation: Toll-like receptors.
    Free Radic Biol Med. 2010 May 1;48(9):1121-32 PMID: 20083193
  12. Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease.
    Brain. 2008 Jul;131(Pt 7):1880-94 PMID: 18504291
  13. Upregulation of activating transcription factor 3 (ATF3) by intrinsic CNS neurons regenerating axons into peripheral nerve grafts.
    Exp Neurol. 2005 Apr;192(2):340-7 PMID: 15755551
  14. ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation.
    Eur J Neurosci. 2005 Oct;22(8):1881-94 PMID: 16262628
  15. Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1.
    Hum Mol Genet. 2008 Feb 15;17(4):602-16 PMID: 18003639
  16. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin.
    Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8 PMID: 16818890
  17. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator.
    Anat Rec. 1991 Dec;231(4):482-97 PMID: 1793176
  18. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism.
    Neurosci Lett. 2008 Aug 22;441(2):158-62 PMID: 18582534
  19. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.
    Nature. 2006 May 11;441(7090):173-8 PMID: 16688168
  20. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses.
    J Immunol. 2006 Feb 1;176(3):1899-907 PMID: 16424221
  21. ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line.
    Brain Res. 2009 Aug 25;1286:221-9 PMID: 19559011
  22. Signaling by ROS drives inflammasome activation.
    Eur J Immunol. 2010 Mar;40(3):616-9 PMID: 20201014
  23. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease.
    Neurosci Lett. 1996 Jun 14;211(1):13-6 PMID: 8809836
  24. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.
    PLoS Biol. 2007 Jul;5(7):e172 PMID: 17579517
  25. Differential effects of methamphetamine and SCH23390 on the expression of members of IEG families of transcription factors in the rat striatum.
    Brain Res. 2010 Mar 8;1318:1-10 PMID: 20059987
  26. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients.
    Neurosci Lett. 1994 Jan 3;165(1-2):208-10 PMID: 8015728
  27. Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity.
    J Neurosci. 2006 Jan 4;26(1):143-51 PMID: 16399681
  28. Axotomy-induced dopaminergic neurodegeneration is accompanied with c-Jun phosphorylation and activation transcription factor 3 expression.
    Exp Neurol. 2008 Jan;209(1):268-78 PMID: 18036593
  29. MAP kinase phosphatase 1 is expressed and enhanced by FK506 in surviving mamillary, but not degenerating nigral neurons following axotomy.
    Brain Res. 1998 Aug 10;801(1-2):198-205 PMID: 9729383
  30. Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data.
    J Cereb Blood Flow Metab. 2002 Feb;22(2):232-9 PMID: 11823721
  31. ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration.
    J Neurosci. 2007 Jul 25;27(30):7911-20 PMID: 17652582
  32. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons.
    J Biol Chem. 1999 Mar 26;274(13):8531-8 PMID: 10085086
  33. 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
  34. Mitochondrial autophagy as a compensatory response to PINK1 deficiency.
    Autophagy. 2009 Nov;5(8):1213-4 PMID: 19786829
  35. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2274-9 PMID: 16461893
  36. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons.
    PLoS One. 2008 Jun 18;3(6):e2455 PMID: 18560593
  37. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease.
    Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):665-70 PMID: 14704277
  38. Practical considerations for the use of the optical disector in estimating neuronal number.
    J Neurosci Methods. 1994 Jan;51(1):83-9 PMID: 8189753
  39. Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis.
    J Bioenerg Biomembr. 2009 Dec;41(6):473-9 PMID: 20012177
  40. Negative regulation of TLR-signaling pathways by activating transcription factor-3.
    J Immunol. 2007 Sep 15;179(6):3622-30 PMID: 17785797
  41. Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.
    Mol Ther. 2008 Sep;16(9):1572-9 PMID: 18628756
  42. Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor.
    J Biol Chem. 2004 Sep 17;279(38):39541-54 PMID: 15252041
  43. The PINK1/Parkin pathway regulates mitochondrial morphology.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43 PMID: 18230723
  44. Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death.
    FASEB J. 2004 Jul;18(10):1162-4 PMID: 15132987
  45. JunB and Bcl-2 overexpression results in protection against cell death of nigral neurons following axotomy.
    Brain Res Mol Brain Res. 2002 Aug 15;104(2):194-202 PMID: 12225874
  46. Over expression of ATF-3 protects rat hippocampal neurons from in vivo injection of kainic acid.
    Brain Res Mol Brain Res. 2004 May 19;124(2):199-203 PMID: 15135228
  47. Akt signal transduction dysfunction in Parkinson's disease.
    Neurosci Lett. 2009 Dec 18;467(1):30-5 PMID: 19800394
  48. 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
  49. A role for dopamine D2 receptors in reversal learning.
    Neuroscience. 2009 Aug 4;162(1):118-27 PMID: 19401217
  50. DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response.
    J Immunol. 2006 Dec 1;177(11):7497-504 PMID: 17114416
  51. Death receptor signal transducers: nodes of coordination in immune signaling networks.
    Nat Immunol. 2009 Apr;10(4):348-55 PMID: 19295631
  52. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway.
    J Biol Chem. 2004 Jul 30;279(31):32869-81 PMID: 15155767
  53. L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset.
    Neuroscience. 2000;99(3):457-68 PMID: 11029538
  54. Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation.
    J Biol Chem. 2008 Jul 25;283(30):21011-23 PMID: 18508759
  55. Nuclear factor-kappaB activation is not involved in a MPTP model of Parkinson's disease.
    Neuroreport. 2001 Apr 17;12(5):1049-53 PMID: 11303744
  56. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.
    Hum Mol Genet. 2005 Nov 15;14(22):3477-92 PMID: 16207731
  57. Glycogen synthase kinase-3beta is associated with Parkinson's disease.
    Neurosci Lett. 2009 Jan 9;449(2):103-7 PMID: 19007860
  58. 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
  59. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis.
    Neuron. 1994 Jan;12(1):139-53 PMID: 7507336
  60. Intrinsic differences in brain and spinal cord mitochondria: Implication for therapeutic interventions.
    J Comp Neurol. 2004 Jul 5;474(4):524-34 PMID: 15174070
  61. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha.
    FASEB J. 2006 Apr;20(6):670-82 PMID: 16581975
  62. TRAIL receptor mediates inflammatory cytokine release in an NF-kappaB-dependent manner.
    Cell Res. 2009 Jun;19(6):758-67 PMID: 19434100
  63. Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease.
    Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18754-9 PMID: 18000063
  64. Cyclic exercise induces anti-inflammatory signal molecule increases in the plasma of Parkinson's patients.
    Int J Mol Med. 2003 Oct;12(4):485-92 PMID: 12964024
  65. Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies.
    J Neural Transm (Vienna). 2001;108(12):1383-96 PMID: 11810403
  66. Regulation and function of NF-kappaB transcription factors in the immune system.
    Annu Rev Immunol. 2009;27:693-733 PMID: 19302050
  67. Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease.
    FASEB J. 2002 Sep;16(11):1474-6 PMID: 12205053
  68. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis.
    J Clin Invest. 2008 Jan;118(1):111-23 PMID: 18079962
  69. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling.
    Hum Mol Genet. 2010 Jan 15;19(2):352-63 PMID: 19880420
  70. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation.
    Biochem Biophys Res Commun. 2008 Dec 19;377(3):975-80 PMID: 18957282
  71. 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
  72. Specific pathophysiological functions of JNK isoforms in the brain.
    Eur J Neurosci. 2005 Jan;21(2):363-77 PMID: 15673436
  73. Human interleukin-10 gene transfer is protective in a rat model of Parkinson's disease.
    Mol Ther. 2008 Aug;16(8):1392-9 PMID: 18545225
  74. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.
    Nature. 2006 Jun 29;441(7097):1162-6 PMID: 16672981
  75. Roles for NF-kappaB in nerve cell survival, plasticity, and disease.
    Cell Death Differ. 2006 May;13(5):852-60 PMID: 16397579
  76. Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide.
    Brain Res Dev Brain Res. 2002 Jan 31;133(1):27-35 PMID: 11850061
  77. Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia.
    Glia. 2005 Aug 15;51(3):199-208 PMID: 15800925
  78. Early and late molecular events occurring following neuronal degeneration in the dopamine system.
    Adv Neurol. 1993;60:316-20 PMID: 8093580
  79. Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.
    Neurobiol Dis. 2010 Mar;37(3):510-8 PMID: 19913097
  80. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.
    Nat Cell Biol. 2010 Feb;12(2):119-31 PMID: 20098416
  81. Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1).
    J Neurochem. 2008 Apr;105(1):18-33 PMID: 18221368
  82. Regulation of innate immune responses in the brain.
    Nat Rev Immunol. 2009 Jun;9(6):429-39 PMID: 19461673
  83. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
    Nature. 2006 Jun 29;441(7097):1157-61 PMID: 16672980
  84. Synaptic mitochondria are more susceptible to Ca2+overload than nonsynaptic mitochondria.
    J Biol Chem. 2006 Apr 28;281(17):11658-68 PMID: 16517608
  85. Glycogen synthase kinase 3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH: implications for proteasomal function and Lewy body formation.
    J Biol Chem. 2005 Dec 30;280(52):42877-86 PMID: 16174773
  86. Parkin deficiency increases vulnerability to inflammation-related nigral degeneration.
    J Neurosci. 2008 Oct 22;28(43):10825-34 PMID: 18945890
  87. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65.
    J Biol Chem. 2003 Jan 24;278(4):2758-66 PMID: 12419806
  88. Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IkappaBalpha-NF-kappaB signaling pathway.
    Mol Cell Biochem. 2008 Aug;315(1-2):41-9 PMID: 18498042
  89. Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra.
    Neurobiol Dis. 2006 Oct;24(1):183-93 PMID: 16901708
  90. FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation.
    Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5153-8 PMID: 19276113
  91. Novel anti-inflammatory role for glycogen synthase kinase-3beta in the inhibition of tumor necrosis factor-alpha- and interleukin-1beta-induced inflammatory gene expression.
    J Biol Chem. 2006 Jun 23;281(25):16985-16990 PMID: 16601113
  92. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10.
    Mol Cell Biol. 1996 Mar;16(3):1157-68 PMID: 8622660
  93. Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila.
    Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10345-50 PMID: 16002472
  94. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
    PLoS Biol. 2010 Jan 26;8(1):e1000298 PMID: 20126261
  95. Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs.
    Cell Death Differ. 2010 Jan;17(1):35-45 PMID: 19680262
  96. Amphiregulin is a mitogen for adult neural stem cells.
    J Neurosci Res. 2002 Sep 15;69(6):757-62 PMID: 12205669
  97. Calcium, ageing, and neuronal vulnerability in Parkinson's disease.
    Lancet Neurol. 2007 Oct;6(10):933-8 PMID: 17884683
  98. Dopamine turnover and glutathione oxidation: implications for Parkinson disease.
    Proc Natl Acad Sci U S A. 1989 Feb;86(4):1398-400 PMID: 2919185
  99. p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain.
    Neurosci Lett. 2007 Feb 27;414(1):94-7 PMID: 17196747
  100. Interleukin-1beta promotes repair of the CNS.
    J Neurosci. 2001 Sep 15;21(18):7046-52 PMID: 11549714
  101. GSK-3 represses growth factor-inducible genes by inhibiting NF-kappaB in quiescent cells.
    J Biol Chem. 2010 Feb 12;285(7):4472-80 PMID: 20018891
  102. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3).
    Trends Immunol. 2010 Jan;31(1):24-31 PMID: 19836308
  103. Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators.
    Blood. 2004 Mar 15;103(6):2135-42 PMID: 14630807
  104. Expression of ATF3 and axonal outgrowth are impaired after delayed nerve repair.
    BMC Neurosci. 2008 Sep 18;9:88 PMID: 18801180
  105. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients.
    Neurosci Lett. 1994 Oct 24;180(2):147-50 PMID: 7700568
  106. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.
    J Neurosci. 2002 Mar 1;22(5):1763-71 PMID: 11880505
  107. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway.
    Science. 1993 Mar 26;259(5103):1912-5 PMID: 8096091
  108. Hereditary early-onset Parkinson's disease caused by mutations in PINK1.
    Science. 2004 May 21;304(5674):1158-60 PMID: 15087508
  109. PINK1 mutations are associated with sporadic early-onset parkinsonism.
    Ann Neurol. 2004 Sep;56(3):336-41 PMID: 15349860
  110. 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
  111. TRAIL-R as a negative regulator of innate immune cell responses.
    Immunity. 2004 Dec;21(6):877-89 PMID: 15589175
  112. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.
    Neurology. 2005 Jul 12;65(1):87-95 PMID: 16009891
  113. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock.
    J Exp Med. 2006 Jan 23;203(1):15-20 PMID: 16380512
  114. DARPP-32: an integrator of neurotransmission.
    Annu Rev Pharmacol Toxicol. 2004;44:269-96 PMID: 14744247
  115. Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation.
    J Neurosci. 2003 Jun 15;23(12):5187-96 PMID: 12832543
  116. Circulating interleukin-10 and interleukin-12 in Parkinson's disease.
    Acta Neurol Scand. 2009 May;119(5):332-7 PMID: 18976327
  117. TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes.
    Immunol Rev. 2009 Mar;228(1):225-40 PMID: 19290931
  118. Identification of NF-kappa B-regulated genes induced by TNFalpha utilizing expression profiling and RNA interference.
    Oncogene. 2003 Apr 3;22(13):2054-64 PMID: 12673210
  119. Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty.
    J Neurosci. 1998 Dec 15;18(24):10579-93 PMID: 9852594
  120. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission.
    J Biol Chem. 2009 May 15;284(20):13843-13855 PMID: 19279012
  121. The regulation of ATF3 gene expression by mitogen-activated protein kinases.
    Biochem J. 2007 Jan 15;401(2):559-67 PMID: 17014422
  122. Expression of angiogenic factor Cyr61 during neuronal cell death via the activation of c-Jun N-terminal kinase and serum response factor.
    J Biol Chem. 2003 Apr 18;278(16):13847-54 PMID: 12576482
  123. Prolonged and selective induction of Fos-related antigen(s) in striatal neurons after 6-hydroxydopamine lesions of the rat substantia nigra pars compacta.
    Brain Res Mol Brain Res. 1991 Jul;10(4):355-8 PMID: 1681407
  124. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention.
    Exp Neurol. 2007 Nov;208(1):1-25 PMID: 17720159
  125. DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice.
    Mol Ther. 2007 Apr;15(4):698-704 PMID: 17299411
  126. Proteasome inhibitors enhance TRAIL-induced apoptosis through the intronic regulation of DR5: involvement of NF-kappa B and reactive oxygen species-mediated p53 activation.
    J Immunol. 2008 Jun 15;180(12):8030-9 PMID: 18523266
  127. Prolonged expression of Fos-related antigens, Jun B and TrkB in dopamine-denervated striatal neurons.
    Brain Res Mol Brain Res. 1995 Jun;30(2):393-6 PMID: 7637593
  128. HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat.
    Brain Res. 2003 Sep 12;984(1-2):133-42 PMID: 12932847
  129. Forkhead transcription factor FOXO3a is a negative regulator of angiogenic immediate early gene CYR61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia.
    Circ Res. 2007 Feb 16;100(3):372-80 PMID: 17234971
  130. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription.
    Mol Cell Biol. 2005 Oct;25(19):8444-55 PMID: 16166627
  131. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease.
    Nature. 2007 Jun 28;447(7148):1081-6 PMID: 17558391
  132. ATF3 enhances c-Jun-mediated neurite sprouting.
    Brain Res Mol Brain Res. 2003 Dec 12;120(1):38-45 PMID: 14667575
  133. Glycogen synthase kinase-3 beta and tau genes interact in Parkinson's and Alzheimer's diseases.
    Ann Neurol. 2009 Jun;65(6):759-61; author reply 761-2 PMID: 19557862
  134. CREB-binding protein/p300 are transcriptional coactivators of p65.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):2927-32 PMID: 9096323
  135. Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps.
    Apoptosis. 2009 Apr;14(4):478-500 PMID: 19165601
  136. Forebrain-specific neuronal inhibition of nuclear factor-kappaB activity leads to loss of neuroprotection.
    J Neurosci. 2003 Oct 15;23(28):9403-8 PMID: 14561868
  137. 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
  138. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.
    Nat Neurosci. 2001 Nov;4(11):1116-22 PMID: 11600888
  139. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.
    Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23 PMID: 20194754
  140. Mitochondrial dynamics, cell death and the pathogenesis of Parkinson's disease.
    Apoptosis. 2010 Nov;15(11):1336-53 PMID: 20131004
  141. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.
    Nat Immunol. 2005 Aug;6(8):777-84 PMID: 16007092
  142. The involvement of NF-kappaB p65/p52 in the effects of GDNF on DA neurons in early PD rats.
    Brain Res Bull. 2008 Jul 30;76(5):505-11 PMID: 18534259
  143. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme.
    Cell Mol Life Sci. 2008 Oct;65(19):2964-78 PMID: 18535784
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0016038
Published
2011-01-13
Epub
2011-00-13
Pages
e16038
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3020954
Subset
IM
Grants
Wellcome Trust · United Kingdom
NCRR NIH HHS · P20 RR015592 · United States
NCRR NIH HHS · P20 RR15592 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0016038 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