Cellular and Molecular Life Sciences

, Volume 70, Issue 22, pp 4259–4273

The role of inflammation in sporadic and familial Parkinson’s disease

Review

Abstract

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.

Keywords

Parkinson’s disease Immune system Neurogenetics Neuroinflammation Glial cells 

Abbreviations

AD

Alzheimer’s disease

APC

Antigen-presenting cell

α-syn

α-Synuclein

CNS

Central nervous system

COX

Cyclooxygenase

CD

Crohn’s disease

DA

Dopaminergic

EOPD

Early onset Parkinson’s disease

FBXO7

F-box protein 7

GBA

Glucocerebrosidase

GD

Gaucher’s disease

GCase

Glucocerebrosidase

GWAS

Genome wide association study

HLA

Human leukocyte antigen

IBD

Inflammatory bowel disease

IL-1β

Interleukin-1beta

LB

Lewy bodies

LN

Lewy neurites

LPS

Lipopolysaccharide

LRRK2

Leucine-rich repeat kinase 2

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

Multiple sclerosis

NO

Nitric oxide

NR

Nuclear receptor

PD

Parkinson’s disease

PLA2G6

Phospholipase A2 group VI

PPAR

Peroxisome proliferator-activated receptor

ROS

Reactive oxygen species

SN

Substantia nigra

TH

Tyrosine hydroxylase

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor-alpha

VIP

Vasoactive intestinal peptide

References

  1. 1.
    Tolosa E, Wenning G, Poewe W (2006) The diagnosis of Parkinson’s disease. Lancet Neurol 5:75–86PubMedGoogle Scholar
  2. 2.
    Shults CW (2006) Lewy bodies. Proc Natl Acad Sci USA 103:1661–1668PubMedGoogle Scholar
  3. 3.
    Braak H, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201:1–119PubMedGoogle Scholar
  4. 4.
    Edwards LL, Quigley EM, Pfeiffer RF (1992) Gastrointestinal dysfunction in Parkinson’s disease: frequency and pathophysiology. Neurology 42:726–732PubMedGoogle Scholar
  5. 5.
    Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72PubMedGoogle Scholar
  6. 6.
    Hallett PJ, McLean JR, Kartunen A, Langston JW, Isacson O (2012) Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol Dis 47:258–267PubMedGoogle Scholar
  7. 7.
    Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250PubMedGoogle Scholar
  8. 8.
    Gasser T, Hardy J, Mizuno Y (2011) Milestones in PD genetics. Mov Disord 26:1042–1048PubMedGoogle Scholar
  9. 9.
    Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J et al (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42:781–785PubMedGoogle Scholar
  10. 10.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40:955–962PubMedGoogle Scholar
  11. 11.
    Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C et al (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640PubMedGoogle Scholar
  12. 12.
    Zhang FR, Huang W, Chen SM, Sun LD, Liu H et al (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618PubMedGoogle Scholar
  13. 13.
    Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18PubMedGoogle Scholar
  14. 14.
    Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3:216–227PubMedGoogle Scholar
  15. 15.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  16. 16.
    Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015PubMedGoogle Scholar
  17. 17.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedGoogle Scholar
  18. 18.
    Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R et al (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771PubMedGoogle Scholar
  19. 19.
    Oldenborg PA, Gresham HD, Lindberg FP (2001) CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis. J Exp Med 193:855–862PubMedGoogle Scholar
  20. 20.
    Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D et al (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 95:10896–10901PubMedGoogle Scholar
  21. 21.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedGoogle Scholar
  22. 22.
    Depboylu C, Schafer MK, Arias-Carrion O, Oertel WH, Weihe E et al (2011) Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease. J Neuropathol Exp Neurol 70:125–132PubMedGoogle Scholar
  23. 23.
    Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ et al (2011) CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J Neuroinflammation 8:154PubMedGoogle Scholar
  24. 24.
    Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM et al (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31PubMedGoogle Scholar
  25. 25.
    Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER et al (2003) APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 278:48529–48533PubMedGoogle Scholar
  26. 26.
    Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E et al (2012) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127PubMedGoogle Scholar
  27. 27.
    Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV et al (2012) Variant of TREM2 associated with the Risk of Alzheimer’s disease. N Engl J Med 368:107–116PubMedGoogle Scholar
  28. 28.
    Aloisi F, Ria F, Adorini L (2000) Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 21:141–147PubMedGoogle Scholar
  29. 29.
    Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Investig 122:1164–1171PubMedGoogle Scholar
  30. 30.
    Ilieva H, Polymenidou M, Cleveland DW (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187:761–772PubMedGoogle Scholar
  31. 31.
    Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3:637–648PubMedGoogle Scholar
  32. 32.
    Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG et al (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657PubMedGoogle Scholar
  33. 33.
    Czirr E, Wyss-Coray T (2012) The immunology of neurodegeneration. J Clin Investig 122:1156–1163PubMedGoogle Scholar
  34. 34.
    Prehaud C, Megret F, Lafage M, Lafon M (2005) Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 79:12893–12904PubMedGoogle Scholar
  35. 35.
    Boulanger LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64:93–109PubMedGoogle Scholar
  36. 36.
    Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021PubMedGoogle Scholar
  37. 37.
    Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34:269–281PubMedGoogle Scholar
  38. 38.
    Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M et al (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409PubMedGoogle Scholar
  39. 39.
    Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E et al (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15:991–998PubMedGoogle Scholar
  40. 40.
    Teismann P, Tieu K, Choi DK, Wu DC, Naini A et al (2003) Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci USA 100:5473–5478PubMedGoogle Scholar
  41. 41.
    Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L et al (2005) Systemic exposure to paraquat and maneb models early Parkinson’s disease in young adult rats. Neurobiol Dis 20:360–371PubMedGoogle Scholar
  42. 42.
    Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  43. 43.
    Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D et al (2013) Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 3:1393PubMedGoogle Scholar
  44. 44.
    Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P et al (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771PubMedGoogle Scholar
  45. 45.
    Sanchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL et al (2004) Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson’s disease. J Neuroinflammation 1:6PubMedGoogle Scholar
  46. 46.
    McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG et al (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26:9365–9375PubMedGoogle Scholar
  47. 47.
    Koprich JB, Reske-Nielsen C, Mithal P, Isacson O (2008) Neuroinflammation mediated by IL-1beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson’s disease. J Neuroinflammation 5:8PubMedGoogle Scholar
  48. 48.
    Deleidi M, Hallett PJ, Koprich JB, Chung CY, Isacson O (2010) The Toll-like receptor-3 agonist polyinosinic:polycytidylic acid triggers nigrostriatal dopaminergic degeneration. J Neurosci 30:16091–16101PubMedGoogle Scholar
  49. 49.
    Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C et al (2012) S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain J Neurol 135:3336–3347Google Scholar
  50. 50.
    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924PubMedGoogle Scholar
  51. 51.
    Chung CY, Koprich JB, Siddiqi H, Isacson O (2009) Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci 29:3365–3373PubMedGoogle Scholar
  52. 52.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedGoogle Scholar
  53. 53.
    Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95:425–432PubMedGoogle Scholar
  54. 54.
    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M et al (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106:518–526PubMedGoogle Scholar
  55. 55.
    Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain 128:2665–2674PubMedGoogle Scholar
  56. 56.
    Miklossy J, Doudet DD, Schwab C, Yu S, McGeer EG et al (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197:275–283PubMedGoogle Scholar
  57. 57.
    Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y et al (1994) Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci Lett 172:151–154PubMedGoogle Scholar
  58. 58.
    Mogi M, Harada M, Kondo T, Riederer P, Inagaki H et al (1994) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 180:147–150PubMedGoogle Scholar
  59. 59.
    Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K et al (1994) Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 165:208–210PubMedGoogle Scholar
  60. 60.
    Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P et al (1995) Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci Lett 193:129–132PubMedGoogle Scholar
  61. 61.
    Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M et al (1996) 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 211:13–16PubMedGoogle Scholar
  62. 62.
    Mogi M, Kondo T, Mizuno Y, Nagatsu T (2007) p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. Neurosci Lett 414:94–97PubMedGoogle Scholar
  63. 63.
    Shimoji M, Pagan F, Healton EB, Mocchetti I (2009) CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson’s disease. Neurotox Res 16:318–328PubMedGoogle Scholar
  64. 64.
    Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 16:724–739PubMedGoogle Scholar
  65. 65.
    Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52:1–6PubMedGoogle Scholar
  66. 66.
    Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26:6–17PubMedGoogle Scholar
  67. 67.
    Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272PubMedGoogle Scholar
  68. 68.
    Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114:231–241PubMedGoogle Scholar
  69. 69.
    Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB et al (2011) Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson’s disease brains. Neurochem Res 36:1452–1463PubMedGoogle Scholar
  70. 70.
    Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132PubMedGoogle Scholar
  71. 71.
    Chen PS, Peng GS, Li G, Yang S, Wu X et al (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11:1116–1125PubMedGoogle Scholar
  72. 72.
    Ishida Y, Nagai A, Kobayashi S, Kim SU (2006) Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J Neuropathol Exp Neurol 65:66–77PubMedGoogle Scholar
  73. 73.
    Haussermann P, Kuhn W, Przuntek H, Muller T (2001) Integrity of the blood-cerebrospinal fluid barrier in early Parkinson’s disease. Neurosci Lett 300:182–184PubMedGoogle Scholar
  74. 74.
    Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J et al (2005) Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57:176–179PubMedGoogle Scholar
  75. 75.
    Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T et al (2005) Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 57:168–175PubMedGoogle Scholar
  76. 76.
    Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21:404–412PubMedGoogle Scholar
  77. 77.
    Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA et al (2010) [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 16:57–59PubMedGoogle Scholar
  78. 78.
    Politis M, Su P, Piccini P (2012) Imaging of microglia in patients with neurodegenerative disorders. Front Pharmacol 3:96PubMedGoogle Scholar
  79. 79.
    Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE (2012) Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009381PubMedGoogle Scholar
  80. 80.
    Fiszer U, Mix E, Fredrikson S, Kostulas V, Link H (1994) Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol Scand 90:160–166PubMedGoogle Scholar
  81. 81.
    Fiszer U, Mix E, Fredrikson S, Kostulas V, Olsson T et al (1994) Gamma delta+ T cells are increased in patients with Parkinson’s disease. J Neurol Sci 121:39–45PubMedGoogle Scholar
  82. 82.
    Bas J, Calopa M, Mestre M, Mollevi DG, Cutillas B et al (2001) Lymphocyte populations in Parkinson’s disease and in rat models of Parkinsonism. J Neuroimmunol 113:146–152PubMedGoogle Scholar
  83. 83.
    Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T (2005) Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 11:493–498PubMedGoogle Scholar
  84. 84.
    Rentzos M, Nikolaou C, Andreadou E, Paraskevas GP, Rombos A et al (2007) Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease. Acta Neurol Scand 116:374–379PubMedGoogle Scholar
  85. 85.
    Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G et al (2007) Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J Neurochem 101:749–756PubMedGoogle Scholar
  86. 86.
    Maetzler W, Berg D, Synofzik M, Brockmann K, Godau J et al (2011) Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. J Alzheimers Dis 26:171–179PubMedGoogle Scholar
  87. 87.
    Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T et al (2013) Colonic inflammation in Parkinson’s disease. Neurobiol Dis 50:42–48PubMedGoogle Scholar
  88. 88.
    Villaran RF, Espinosa-Oliva AM, Sarmiento M, De Pablos RM, Arguelles S et al (2010) Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson`s disease. J Neurochem 114:1687–1700PubMedGoogle Scholar
  89. 89.
    Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859PubMedGoogle Scholar
  90. 90.
    Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA et al (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334:98–101PubMedGoogle Scholar
  91. 91.
    Wong CH, Jenne CN, Lee WY, Leger C, Kubes P (2011) Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334:101–105PubMedGoogle Scholar
  92. 92.
    Chen H, Zhang SM, Hernan MA, Schwarzschild MA, Willett WC et al (2003) Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 60:1059–1064PubMedGoogle Scholar
  93. 93.
    Ton TG, Heckbert SR, Longstreth WT Jr, Rossing MA, Kukull WA et al (2006) Nonsteroidal anti-inflammatory drugs and risk of Parkinson’s disease. Mov Disord 21:964–969PubMedGoogle Scholar
  94. 94.
    Wahner AD, Bronstein JM, Bordelon YM, Ritz B (2007) Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 69:1836–1842PubMedGoogle Scholar
  95. 95.
    Gao X, Chen H, Schwarzschild MA, Ascherio A (2011) Use of ibuprofen and risk of Parkinson disease. Neurology 76:863–869PubMedGoogle Scholar
  96. 96.
    Rees K, Stowe R, Patel S, Ives N, Breen K et al (2011) Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database Syst Rev 11:CD008454PubMedGoogle Scholar
  97. 97.
    Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM et al (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377:641–649PubMedGoogle Scholar
  98. 98.
    Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM et al (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet 7:e1002141PubMedGoogle Scholar
  99. 99.
    Srinivasan BS, Doostzadeh J, Absalan F, Mohandessi S, Jalili R et al (2009) Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease. Hum Mutat 30:228–238PubMedGoogle Scholar
  100. 100.
    Holmans P, Moskvina V, Jones L, Sharma M, Vedernikov A et al (2012) A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum Mol Genet 22:1039–1049PubMedGoogle Scholar
  101. 101.
    Wahner AD, Sinsheimer JS, Bronstein JM, Ritz B (2007) Inflammatory cytokine gene polymorphisms and increased risk of Parkinson disease. Arch Neurol 64:836–840PubMedGoogle Scholar
  102. 102.
    Lin JJ, Chen CH, Yueh KC, Chang CY, Lin SZ (2006) A CD14 monocyte receptor polymorphism and genetic susceptibility to Parkinson’s disease for females. Parkinsonism Relat Disord 12:9–13PubMedGoogle Scholar
  103. 103.
    Bialecka M, Kurzawski M, Klodowska-Duda G, Opala G, Juzwiak S et al (2007) CARD15 variants in patients with sporadic Parkinson’s disease. Neurosci Res 57:473–476PubMedGoogle Scholar
  104. 104.
    Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A et al (2012) Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology 79:659–667PubMedGoogle Scholar
  105. 105.
    Miklossy J, Arai T, Guo JP, Klegeris A, Yu S et al (2006) LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol 65:953–963PubMedGoogle Scholar
  106. 106.
    Melrose HL, Kent CB, Taylor JP, Dachsel JC, Hinkle KM et al (2007) A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. Neuroscience 147:1047–1058PubMedGoogle Scholar
  107. 107.
    Gardet A, Benita Y, Li C, Sands BE, Ballester I et al (2010) LRRK2 Is involved in the IFN-{gamma} response and host response to pathogens. J Immunol 185:5577–5585PubMedGoogle Scholar
  108. 108.
    Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y et al (2011) Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm 118:795–808PubMedGoogle Scholar
  109. 109.
    Kim B, Yang MS, Choi D, Kim JH, Kim HS et al (2012) Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. PLoS ONE 7:e34693PubMedGoogle Scholar
  110. 110.
    Gillardon F, Schmid R, Draheim H (2012) Parkinson’s disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208:41–48PubMedGoogle Scholar
  111. 111.
    Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG et al (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611PubMedGoogle Scholar
  112. 112.
    Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R et al (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci USA 107:9879–9884PubMedGoogle Scholar
  113. 113.
    Liu Z, Lee J, Krummey S, Lu W, Cai H et al (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12:1063–1070PubMedGoogle Scholar
  114. 114.
    Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–1661PubMedGoogle Scholar
  115. 115.
    Allen MJ, Myer BJ, Khokher AM, Rushton N, Cox TM (1997) Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: increased release of interleukin-6 and interleukin-10. Q J Med 90:19–25Google Scholar
  116. 116.
    Mizukami H, Mi Y, Wada R, Kono M, Yamashita T et al (2002) Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. J Clin Investig 109:1215–1221PubMedGoogle Scholar
  117. 117.
    Barak V, Acker M, Nisman B, Kalickman I, Abrahamov A et al (1999) Cytokines in Gaucher’s disease. Eur Cytokine Netw 10:205–210PubMedGoogle Scholar
  118. 118.
    Hollak CE, Evers L, Aerts JM, van Oers MH (1997) Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood Cells Mol Dis 23:201–212PubMedGoogle Scholar
  119. 119.
    Farfel-Becker T, Vitner EB, Pressey SN, Eilam R, Cooper JD et al (2011) Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. Hum Mol Genet 20:1375–1386PubMedGoogle Scholar
  120. 120.
    Vitner EB, Farfel-Becker T, Eilam R, Biton I, Futerman AH (2012) Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain J Neurol 135:1724–1735Google Scholar
  121. 121.
    Mistry PK, Liu J, Yang M, Nottoli T, McGrath J et al (2010) Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl Acad Sci USA 107:19473–19478PubMedGoogle Scholar
  122. 122.
    Liu J, Halene S, Yang M, Iqbal J, Yang R et al (2012) Gaucher disease gene GBA functions in immune regulation. Proc Natl Acad Sci USA 109:10018–10023PubMedGoogle Scholar
  123. 123.
    Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I et al (2011) GBA-associated PD presents with nonmotor characteristics. Neurology 77:276–280PubMedGoogle Scholar
  124. 124.
    Holmes C, Cunningham C, Zotova E, Woolford J, Dean C et al (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774PubMedGoogle Scholar
  125. 125.
    Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H et al (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16:394–406PubMedGoogle Scholar
  126. 126.
    Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM et al (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain J Neurol 127:420–430Google Scholar
  127. 127.
    Neumann M, Muller V, Gorner K, Kretzschmar HA, Haass C et al (2004) 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 107:489–496PubMedGoogle Scholar
  128. 128.
    van Horssen J, Drexhage JA, Flor T, Gerritsen W, van der Valk P et al (2010) Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med 49:1283–1289PubMedGoogle Scholar
  129. 129.
    Mullett SJ, Hamilton RL, Hinkle DA (2009) DJ-1 immunoreactivity in human brain astrocytes is dependent on infarct presence and infarct age. Neuropathology 29:125–131PubMedGoogle Scholar
  130. 130.
    Waak J, Weber SS, Waldenmaier A, Gorner K, Alunni-Fabbroni M et al (2009) Regulation of astrocyte inflammatory responses by the Parkinson’s disease-associated gene DJ-1. FASEB J 23:2478–2489PubMedGoogle Scholar
  131. 131.
    Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) Alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14PubMedGoogle Scholar
  132. 132.
    Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol 176:98–104PubMedGoogle Scholar
  133. 133.
    Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H et al (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain J Neurol 127:2657–2671Google Scholar
  134. 134.
    Togo T, Dickson DW (2002) Tau accumulation in astrocytes in progressive supranuclear palsy is a degenerative rather than a reactive process. Acta Neuropathol 104:398–402PubMedGoogle Scholar
  135. 135.
    Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20PubMedGoogle Scholar
  136. 136.
    Beraud D, Twomey M, Bloom B, Mittereder A, Ton V et al (2011) Alpha-synuclein alters toll-like receptor expression. Front Neurosci 5:80PubMedGoogle Scholar
  137. 137.
    Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W et al (2011) Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 179:954–963PubMedGoogle Scholar
  138. 138.
    Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L et al (2012) Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61:349–360PubMedGoogle Scholar
  139. 139.
    Gu XL, Long CX, Sun L, Xie C, Lin X et al (2010) Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 3:12PubMedGoogle Scholar
  140. 140.
    Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ et al (2003) 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 USA 100:2884–2889PubMedGoogle Scholar
  141. 141.
    Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M (2010) Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS ONE 5:e8784PubMedGoogle Scholar
  142. 142.
    Lastres-Becker I, Ulusoy A, Innamorato NG, Sahin G, Rabano A et al (2012) Alpha-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Hum Mol Genet 21:3173–3192PubMedGoogle Scholar
  143. 143.
    Theodore S, Cao S, McLean PJ, Standaert DG (2008) Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 67:1149–1158PubMedGoogle Scholar
  144. 144.
    Watson MB, Richter F, Lee SK, Gabby L, Wu J et al (2012) Regionally-specific microglial activation in young mice over-expressing human wild-type alpha-synuclein. Exp Neurol 237:318–334PubMedGoogle Scholar
  145. 145.
    Klegeris A, Giasson BI, Zhang H, Maguire J, Pelech S et al (2006) Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB J 20:2000–2008PubMedGoogle Scholar
  146. 146.
    Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H et al (2008) Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging 29:739–752PubMedGoogle Scholar
  147. 147.
    Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T et al (2008) Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacology 3:59–74Google Scholar
  148. 148.
    Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K et al (2008) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29:1690–1701PubMedGoogle Scholar
  149. 149.
    Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Fernandez-Montesinos R, Caro M et al (2010) Glial innate immunity generated by non-aggregated alpha-synuclein in mouse: differences between wild-type and Parkinson’s disease-linked mutants. PLoS ONE 5:e13481PubMedGoogle Scholar
  150. 150.
    Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A et al (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 104:1504–1525PubMedGoogle Scholar
  151. 151.
    Zhang W, Wang T, Pei Z, Miller DS, Wu X et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542PubMedGoogle Scholar
  152. 152.
    Su X, Federoff HJ, Maguire-Zeiss KA (2009) Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox Res 16:238–254PubMedGoogle Scholar
  153. 153.
    Chung CY, Koprich JB, Hallett PJ, Isacson O (2009) Functional enhancement and protection of dopaminergic terminals by RAB3B overexpression. Proc Natl Acad Sci USA 106:22474–22479PubMedGoogle Scholar
  154. 154.
    Le WD, Xu P, Jankovic J, Jiang H, Appel SH et al (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89PubMedGoogle Scholar
  155. 155.
    Zheng K, Heydari B, Simon DK (2003) A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Arch Neurol 60:722–725PubMedGoogle Scholar
  156. 156.
    Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH (1999) Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126:4017–4026PubMedGoogle Scholar
  157. 157.
    Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:e002PubMedGoogle Scholar
  158. 158.
    Pei L, Castrillo A, Chen M, Hoffmann A, Tontonoz P (2005) Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J Biol Chem 280:29256–29262PubMedGoogle Scholar
  159. 159.
    Mages HW, Rilke O, Bravo R, Senger G, Kroczek RA (1994) NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mol Endocrinol 8:1583–1591PubMedGoogle Scholar
  160. 160.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L et al (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59PubMedGoogle Scholar
  161. 161.
    Luo Y, Henricksen LA, Giuliano RE, Prifti L, Callahan LM et al (2007) VIP is a transcriptional target of Nurr1 in dopaminergic cells. Exp Neurol 203:221–232PubMedGoogle Scholar
  162. 162.
    Delgado M, Ganea D (2003) Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J 17:944–946PubMedGoogle Scholar
  163. 163.
    Katan M, Moon YP, Paik MC, Sacco RL, Wright CB et al (2013) Infectious burden and cognitive function: The Northern Manhattan study. Neurology 80:1209–1215PubMedGoogle Scholar
  164. 164.
    Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289:2819–2826PubMedGoogle Scholar
  165. 165.
    Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI et al (2006) Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 60:22–31PubMedGoogle Scholar
  166. 166.
    Plane JM, Shen Y, Pleasure DE, Deng W (2010) Prospects for minocycline neuroprotection. Arch Neurol 67:1442–1448PubMedGoogle Scholar
  167. 167.
    Diguet E, Fernagut PO, Wei X, Du Y, Rouland R et al (2004) Deleterious effects of minocycline in animal models of Parkinson’s disease and Huntington’s disease. Eur J Neurosci 19:3266–3276PubMedGoogle Scholar
  168. 168.
    NINDS NET-PT Investigators (2006) A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66:664–671Google Scholar
  169. 169.
    Drouin-Ouellet J, Cicchetti F (2012) Inflammation and neurodegeneration: the story ‘retolled’. Trends Pharmacol Sci 33:542–551PubMedGoogle Scholar
  170. 170.
    Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, Sullivan PG, Bueler, H (2011) Increased mitochondrial calcium sensitivity abnormal expression of innate immunity genes precede dopaminergic defects in Pink1–deficient mice. PLoS ONE 6:e16038Google Scholar
  171. 171.
    Xu X, Li D, He Q, Gao J, Chen B, Xie A (2011) Interleukin–18 promoter polymorphisms risk of Parkinson's disease in a Han Chinese population. Brain Res 1381:90–94Google Scholar
  172. 172.
    Wu YR, Feng IH, Lyu RK, Chang KH, Lin YY, Chan H, Hu FJ, Lee–Chen GJ. Chen CM (2007b) Tumor necrosis factor–alpha promoter polymorphism is associated with the risk of Parkinson's disease. Am J Medical Genet B 144B:300–304Google Scholar
  173. 173.
    Wu YR, Chen CM, Hwang JC et al (2007a) Interleukin–1 alpha polymorphism has influence on late–onset sporadic Parkinson's disease in Taiwan. J Neural Transm 114:1173–1177Google Scholar
  174. 174.
    Wilhelmus MM, van der Pol SM, Jansen Q, Witte ME, van der Valk P, Rozemuller J, Drukarch B, de Vries HE, Van Horssen J (2011) Association of Parkinson disease–related protein PINK1 with Alzheimer disease multiple sclerosis brain lesions. Free Radic Biol Med 50:469–476Google Scholar
  175. 175.
    Tran TA, Nguyen AD, Chang J, Goldberg MS, Lee JK, Tansey MG (2011) Lipopolysaccharide tumor necrosis factor regulate Parkin expression via nuclear factor–kappa B. PLoS ONE 6:e23660Google Scholar
  176. 176.
    Schulte T, Schols L, Muller T, Woitalla D, Berger K, Kruger R (2002) Polymorphisms in the interleukin–1 alpha beta genes the risk for Parkinson's disease. Neurosci Lett 326:70–72Google Scholar
  177. 177.
    Saiki M, Baker A, Williams–Gray CH et al (2010) Association of the human leucocyte antigen region with susceptibility to Parkinson's disease. J Neurol Neurosurg Psychiatry 81:890–891Google Scholar
  178. 178.
    Ross OA, O'Neill C, Rea IM, Lynch T, Gosal D, Wallace A, Curran MD, Middleton D, Gibson JM (2004) Functional promoter region polymorphism of the proinflammatory chemokine IL–8 gene associates with Parkinson's disease in the Irish. Hum Immunol 65:340–346Google Scholar
  179. 179.
    Rosenbloom BE, Weinreb NJ, Zimran A, Kacena KA, Charrow J, Ward E (2005) Gaucher disease cancer incidence: a study from the Gaucher Registry. Blood 105:4569–4572Google Scholar
  180. 180.
    Puschmann A, Verbeeck C, Heckman MG et al (2011) Human leukocyte antigen variation Parkinson's disease. Parkinsonism Related Disord 17:376–378Google Scholar
  181. 181.
    Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172Google Scholar
  182. 182.
    Nishimura M, Mizuta I, Mizuta E, Yamasaki S, Ohta M, Kuno S (2000) Influence of interleukin–1beta gene polymorphisms on age–at–onset of sporadic Parkinson's disease. Neurosci Lett 284:73–76Google Scholar
  183. 183.
    Nishimura M, Mizuta I, Mizuta E, Yamasaki S, Ohta M, Kaji R, Kuno S (2001) Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease. Neurosci Lett 311:1–4Google Scholar
  184. 184.
    McGeer PL, Yasojima K, McGeer EG (2002) Association of interleukin–1 beta polymorphisms with idiopathic Parkinson's disease. Neurosci Lett 326:67–69Google Scholar
  185. 185.
    Mattila KM, Rinne JO, Lehtimaki T, Roytta M, Ahonen JP, Hurme M (2002) Association of an interleukin 1B gene polymorphism (–511) with Parkinson's disease in Finnish patients. J Med Genet 39:400–402Google Scholar
  186. 186.
    Marodi L, Kaposzta R, Toth J, Laszlo A (1995) Impaired microbicidal capacity of mononuclear phagocytes from patients with type I Gaucher disease: partial correction by enzyme replacement therapy. Blood 86:4645–4649Google Scholar
  187. 187.
    Lill CM, Roehr JT, McQueen MB et al (2012) Comprehensive research synopsis systematic meta–analyses in Parkinson's disease genetics: The PDGene database. PLoS Genet 8:e1002548Google Scholar
  188. 188.
    Ledesma, MD, Galvan C, Hellias B, Dotti C, Jensen PH (2002) Astrocytic but not neuronal increased expression redistribution of parkin during unfolded protein stress. J Neurochem 83:1431–1440Google Scholar
  189. 189.
    Lampe JB, Gossrau G, Herting B, Kempe A, Sommer U, Fussel M, Weber M, Koch R, Reichmann H (2003) HLA typing Parkinson's disease. Eur Neurol 50:64–68Google Scholar
  190. 190.
    Kruger R, Hardt C, Tschentscher F et al (2000) Genetic analysis of immunomodulating factors in sporadic Parkinson's disease. J Neural Transm 107:553–562Google Scholar
  191. 191.
    Hakansson A, Westberg L, Nilsson S et al (2005b) Investigation of genes coding for inflammatory components in Parkinson's disease. Mov Disord 20:569–573Google Scholar
  192. 192.
    Hakansson A, Westberg L, Nilsson S et al (2005a) Interaction of polymorphisms in the genes encoding interleukin–6 estrogen receptor beta on the susceptibility to Parkinson's disease. Am J Med Genet B 133B:88–92Google Scholar
  193. 193.
    Guo Y, Deng X, Zheng W et al (2011) HLA rs3129882 variant in Chinese Han patients with late–onset sporadic Parkinson disease. Neurosci Lett 501:185–187Google Scholar
  194. 194.
    Greene JC, Whitworth AJ, Andrews LA, Parker TJ, Pallanck LJ (2005) Genetic genomic studies of Drosophila parkin mutants implicate oxidative stress innate immune responses in pathogenesis. Human Mol Genet 14:799–811Google Scholar
  195. 195.
    Frank-Cannon TC, Tran T, Ruhn KA (2008) Parkin deficiency increases vulnerability to inflammation–related nigral degeneration. J Neurosci 28:10825–10834Google Scholar
  196. 196.
    Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ–1, a cancer– Parkinson's disease–associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096Google Scholar
  197. 197.
    Bialecka M, Klodowska–Duda G, Kurzawski M, Slawek J, Gorzkowska A, Opala G, Bialecki P, Sagan L, Drozdzik M (2008) Interleukin–10 (IL10) tumor necrosis factor alpha (TNF) gene polymorphisms in Parkinson's disease patients. Parkinsonism Related Disord 14:636–640Google Scholar
  198. 198.
    Balsinde J, Balboa MA (2005) Cellular regulation proposed biological functions of group VIA calcium–independent phospholipase A2 in activated cells. Cell Signal 17:1052–1062Google Scholar
  199. 199.
    Austin SA, Floden AM, Murphy EJ, Combs CK (2006) Alpha–synuclein expression modulates microglial activation phenotype. J Neurosci 26:10558–10563Google Scholar
  200. 200.
    Zhou YT, Yang JF, Zhang YL, Wang XY, Chan P (2008) Protective role of interlekin-1 alpha gene polymorphism in Chinese Han population with sporadic Parkinson's disease. Neurosci Lett 445:23–25Google Scholar
  201. 201.
    Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611Google Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.German Center for Neurodegenerative Diseases (DZNE)TübingenGermany
  2. 2.Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany

Personalised recommendations