Integrating pathways of parkinson's disease in a molecular interaction map

Molecular Neurobiology

Volumn 49, Issue 1, 2014, Pages 88-102

  Fujita, Kazuhiro A ^a   Ostaszewski, Marek ^b,c   Matsuoka, Yukiko ^a   Ghosh, Samik ^a   Glaab, Enrico ^b   Trefois, Christophe ^b   Crespo, Isaac ^b   Perumal, Thanneer M ^b   Jurkowski, Wiktor ^b   Antony, Paul M A ^b   Diederich, Nico ^b,d   Buttini, Manuel ^b   Kodama, Akihiko ^e   Satagopam, Venkata P ^b,f   Eifes, Serge ^b   Del Sol, Antonio ^b   Schneider, Reinhard ^b,f   Kitano, Hiroaki ^a,g,h,i   Balling, Rudi ^b  

^a Systems Biology Institute   (Japan)

^b UNIVERSITY OF LUXEMBOURG   (Luxembourg)

^c INTEGRATED BIOBANK OF LUXEMBOURG   (Luxembourg)

^d CENTRE HOSPITALIER DE LUXEMBOURG   (Luxembourg)

^e TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

^f EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

^g SONY COMPUTER SCIENCE LABORATORIES INC   (Japan)

^h CANCER INSTITUTE   (Japan)

ⁱ OKINAWA INSTITUTE OF SCIENCE AND TECHNOLOGY GRADUATE UNIVERSITY   (Japan)

Author keywords

Bioinformatics; Knowledge repository; Molecular neuropathology; Parkinson's disease

Indexed keywords

ALPHA SYNUCLEIN; APOPTOSOME; CASPASE 3; CASPASE 7; DOPAMINE; OLIGOMER; PARKIN; PROTEASOME;

APOPTOSIS; ASTROCYTE; BIOINFORMATICS; BRAIN MITOCHONDRION; CALCIUM TRANSPORT; COMPUTER PROGRAM; CORPUS STRIATUM; DOPAMINE METABOLISM; DOPAMINERGIC NERVE CELL; ENVIRONMENTAL FACTOR; GENETIC PREDISPOSITION; HUMAN; INNATE IMMUNITY; MARKUP LANGUAGE; MEDICAL RESEARCH; MESENCEPHALON; MICROGLIA; MITOPHAGY; MOLECULAR INTERACTION; NERVE CELL DEGENERATION; NERVE CELL NECROSIS; NERVOUS SYSTEM INFLAMMATION; NEUROPATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOLOGY; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FOLDING; REVIEW; SUBSTANTIA NIGRA PARS COMPACTA; SYNAPTIC TRANSMISSION; SYSTEMS BIOLOGY; WORKFLOW;

ANIMALS; COMPUTATIONAL BIOLOGY; HUMANS; MESENCEPHALON; NERVE NET; PARKINSON DISEASE; PROTEOLYSIS; SIGNAL TRANSDUCTION;

EID: 84894315212     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-013-8489-4     Document Type: Review

References (265)

1. Obeso JA, Rodriguez-Oroz MC, Goetz CG et al (2010) Missing pieces in the Parkinson's disease puzzle. Nat Med 16:653-661. doi: 10.1038/nm.2165
2. Caron E, Ghosh S, Matsuoka Y et al (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6:453. doi: 10.1038/msb.2010.108
3. Mizuno S, Iijima R, Ogishima S et al (2012) AlzPathway: a comprehensive map of signaling pathways of Alzheimer's disease. BMC Syst Biol 6:52. doi: 10.1186/1752-0509-6-52
4. Ghosh S, Matsuoka Y, Asai Y et al (2011) Software for systems biology: from tools to integrated platforms. Nat Rev Genet 12:821-832
5. Kitano H, Ghosh S, Matsuoka Y (2011) Social engineering for virtual "big science" in systems biology. Nat Chem Biol 7:323-326
6. Lees AJ, Hardy J, Revesz T (2009) Parkinson's disease. Lancet 373:2055-2066. doi: 10.1016/S0140-6736(09)60492-X
7. Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368-376. doi: 10.1136/jnnp.2007.131045
8. Meissner WG, Frasier M, Gasser T et al (2011) Priorities in Parkinson's disease research. Nat Rev Drug Disc 10:377-393. doi: 10.1038/nrd3430
9. Dick FD, De Palma G, Ahmadi A et al (2007) Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study. Occup Environ Med 64:666-672. doi: 10.1136/oem.2006.027003
10. Goldman SM, Tanner CM, Oakes D et al (2006) Head injury and Parkinson's disease risk in twins. Ann Neurol 60:65-72. doi: 10.1002/ana.20882
11. Ritz B, Ascherio A, Checkoway H et al (2007) Pooled analysis of tobacco use and risk of Parkinson disease. Arch Neurol 64:990-997. doi: 10.1001/archneur.64.7.990
12. Hu G, Bidel S, Jousilahti P et al (2007) Coffee and tea consumption and the risk of Parkinson's disease. Mov Disord 22:2242-2248. doi: 10.1002/mds.21706
13. Saunders-Pullman R (2003) Estrogens and Parkinson disease: neuroprotective, symptomatic, neither, or both? Endocrine 21:81-87. doi: 10.1385/ENDO:21:1:81
14. Klein C, Westenberger A (2012) Genetics of Parkinson's disease. Cold Spring Harb Perspect Med 2:a008888. doi: 10.1101/cshperspect.a008888
15. Marques SCF, Oliveira CR, Pereira CMF, Outeiro TF (2011) Epigenetics in neurodegeneration: a new layer of complexity. Prog Neuro-psychopharmacol Biol Psychiatry 35:348-355. doi: 10.1016/j.pnpbp.2010.08.008
16. Migliore L, Coppedè F (2009) Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res 667:82-97. doi: 10.1016/j.mrfmmm.2008.10.011
17. Schapira AHV (2011) Aetiopathogenesis of Parkinson's disease. J Neurol 258:S307-S310. doi: 10.1007/s00415-011-6016-y
18. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS (2001) Environmental risk factors and Parkinson's disease: a metaanalysis. Environ Res 86:122-127. doi: 10.1006/enrs.2001.4264
19. Dick FD (2006) Parkinson's disease and pesticide exposures. Br Med Bull 79-80:219-231. doi: 10.1093/bmb/ldl018
20. Davis GC, Williams AC, Markey SP et al (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249-254
21. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979-980
22. Betarbet R, Sherer TB, MacKenzie G et al (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301-1306. doi: 10.1038/81834
23. Thiruchelvam M, Richfield EK, Baggs RB et al (2000) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J Neurosci 20:9207-9214
24. Gash DM, Rutland K, Hudson NL et al (2008) Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 63:184-192. doi: 10.1002/ana.21288
25. Goldman SM (2010) Trichloroethylene and Parkinson's disease: dissolving the puzzle. Expert Rev Neurother 10:835-837. doi: 10.1586/ern.10.61
26. Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197-211
27. Poulopoulos M, Levy OA, Alcalay RN (2012) The neuropathology of genetic Parkinson's disease. Mov Disord 000:1-12. doi: 10.1002/mds.24962
28. Wolters EC (2009) Non-motor extranigral signs and symptoms in Parkinson's disease. Parkinsonism & Relat Disord 15(Suppl 3):S6-S12. doi: 10.1016/S1353-8020(09)70770-9
29. Ferrer I, López-Gonzalez I, Carmona M et al (2012) Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 46:508-526. doi: 10.1016/j.nbd.2011.10.019
30. Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease. Trends Neurosci 30:244-250. doi: 10.1016/j.tins.2007.03.009
31. Matsuda W, Furuta T, Nakamura KC et al (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 29:444-453
32. Matsuda W (2012) Imaging of dopaminergic neurons and the implications for Parkinson's disease. Syst Biol Parkinson's Dis. doi: 10.1007/978-1-4614-3411-5
33. Parent M, Parent A (2006) Relationship between axonal collateralization and neuronal degeneration in basal ganglia. J Neural Transm Suppl 85-8
34. Schmitz Y, Luccarelli J, Kim M et al (2009) Glutamate controls growth rate and branching of dopaminergic axons. J Neurosci 29:11973-11981. doi: 10.1523/JNEUROSCI.2927-09.2009
35. Braak H, Bohl JR, Müller CM et al (2006) Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord 21:2042-2051. doi: 10.1002/mds.21065
36. Kim-Han JS, Antenor-Dorsey JA, O'Malley KL (2011) The Parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci 31:7212-7221. doi: 10.1523/JNEUROSCI.0711-11.2011
37. Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39:889-909
38. Chan CS, Guzman JN, Ilijic E et al (2007) "Rejuvenation" protects neurons in mouse models of Parkinson's disease. Nature 447:1081-1086. doi: 10.1038/nature05865
39. Surmeier DJ, Guzman JN, Sanchez-Padilla J, Schumacker PT (2011) The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson's disease. Neuroscience 198:221-231
40. Asanuma M, Miyazaki I, Ogawa N (2003) Dopamine- or l-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease. Neurotox Res 5:165-176
41. Cantuti-Castelvetri I, Shukitt-Hale B, Joseph JA (2003) Dopamine neurotoxicity: age-dependent behavioral and histological effects. Neurobiol aging 24:697-706
42. Collier TJ, Kanaan NM, Kordower JH (2011) Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 12:359-366. doi: 10.1038/nrn3039
43. Mosharov EV, Larsen KE, Kanter E et al (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218-229. doi: 10.1016/j.neuron.2009.01.033
44. Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146:682-695. doi: 10.1016/j.cell.2011.07.030
45. Mammucari C, Rizzuto R (2010) Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev 131:536-543. doi: 10.1016/j.mad.2010.07. 003
46. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109-1112. doi: 10.1126/science.1201940
47. Venkateshappa C, Harish G, Mythri RB et al (2012) Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease. Neurochem Res 37:358-369. doi: 10.1007/s11064-011-0619-7
48. Mallucci GR (2009) Prion neurodegeneration: starts and stops at the synapse. Prion 3:195-201
49. Sisková Z, Sanyal NK, Orban A et al (2010) Reactive hypertrophy of synaptic varicosities within the hippocampus of prion-infected mice. Biochem Soc Trans 38:471-475
50. Masliah E (1998) Mechanisms of synaptic pathology in Alzheimer's disease. J Neural Transm Suppl 53:147-158
51. Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13:812-818
52. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:2045-2047
53. Singleton AB, Farrer MJ, Johnson J et al (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302:841. doi: 10.1126/science.1090278
54. Simón-Sánchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41:1308-1312
55. Fortin DL, Nemani VM, Voglmaier SM et al (2005) Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci 25:10913-10921. doi: 10.1523/JNEUROSCI.2922-05.2005
56. Burré J, Sharma M, Tsetsenis T et al (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663-1667
57. Chandra S, Gallardo G, Fernández-Chacón R et al (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383-396
58. Quilty MC, King AE, Gai W-P et al (2006) Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol 199:249-256
59. Nemani VM, Lu W, Berge V et al (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66-79
60. Schulz-Schaeffer WJ (2010) The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathologica 120:131-143
61. Piccoli G, Condliffe SB, Bauer M et al (2011) LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci 31:2225-2237
62. Shin N, Jeong H, Kwon J et al (2008) LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 314:2055-2065
63. Conway KA, Rochet JC, Bieganski RM, Lansbury PT (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346-1349. doi: 10.1126/science.1063522
64. Leong SL, Cappai R, Barnham KJ, Pham CLL (2009) Modulation of alpha-synuclein aggregation by dopamine: a review. Neurochem Res 34:1838-1846
65. Perier C, Vila M (2012) Mitochondrial biology and Parkinson's disease. Cold Spring Harb Perspect Med 2:a009332. doi: 10.1101/cshperspect.a009332
66. Tai H-C, Schuman EM (2008) Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 9:826-838
67. Youle RJ, Van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062-1065. doi: 10.1126/science.1219855
68. Schapira AHV, Cooper JM, Dexter D et al (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 54:823-827
69. Parker WD, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26:719-723. doi: 10.1002/ana.410260606
70. Koopman W, Willems P (2012) Monogenic mitochondrial disorders. New Engl J Med
71. Matsuda N, Sato S, Shiba K et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211-221. doi: 10.1083/jcb.200910140
72. Plun-Favreau H, Klupsch K, Moisoi N et al (2007) The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nature Cell Biol 9:1243-1252. doi: 10.1038/ncb1644
73. Pridgeon JW, Olzmann J a, Chin L-S, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172. doi: 10.1371/journal.pbio.0050172
74. Chan NC, Salazar AM, Pham AH et al (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20:1726-1737. doi: 10.1093/hmg/ddr048
75. Gegg ME, Cooper JM, Chau K-Y et al (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19:4861-4870. doi: 10.1093/hmg/ddq419
76. Geisler S, Holmström KM, Skujat D et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol 12:119-131. doi: 10.1038/ncb2012
77. Shin J-H, Ko HS, Kang H et al (2011) PARIS (ZNF746) Repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell 144:689-702. doi: 10.1016/j.cell.2011.02.010
78. Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88:611-638. doi: 10.1152/physrev.00025.2007
79. Ryan MT, Hoogenraad NJ (2007) Mitochondrial-nuclear communications. Annu Rev Biochem 76:701-722. doi: 10.1146/annurev.biochem.76.052305.091720
80. Gandhi S, Wood-Kaczmar A, Yao Z et al (2009) PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Molecular Cell 33:627-638. doi: 10.1016/j.molcel.2009.02.013
81. Yao Z, Gandhi S, Burchell VS et al (2011) Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease. J Cell Sci 124:4194-4202. doi: 10.1242/jcs.088260
82. Tschopp J (2011) Mitochondria: Sovereign of inflammation? Eur J Immunol 41:1196-1202
83. Thomas KJ, McCoy MK, Blackinton J et al (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20:40-50. doi: 10.1093/hmg/ddq430
84. Burbulla LF, Schelling C, Kato H et al (2010) Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis. Hum Mol Genet 19:4437-4452. doi: 10.1093/hmg/ddq370
85. Yang H, Zhou X, Liu X et al (2011) Mitochondrial dysfunction induced by knockdown of mortalin is rescued by Parkin. Biochem Biophys Res Commun 410:114-120. doi: 10.1016/j.bbrc.2011.05.116
86. Weihofen A, Thomas KJ, Ostaszewski BL et al (2009) Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48:2045-2052. doi: 10.1021/bi8019178
87. Wang X, Winter D, Ashrafi G et al (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893-906. doi: 10.1016/j.cell.2011.10.018
88. Pilsl A, Winklhofer KF (2012) Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson's disease. Acta Neuropathol 123:173-188. doi: 10.1007/s00401-011-0902-3
89. Sheng Z-H, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13:77-93. doi: 10.1038/nrn3156
90. Lee H-J, Khoshaghideh F, Lee S, Lee S-J (2006) Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur J Neurosci 24:3153-3162. doi: 10.1111/j.1460-9568.2006.05210.x
91. Yang F, Jiang Q, Zhao J et al (2005) Parkin stabilizes microtubules through strong binding mediated by three independent domains. J Biol Chem 280:17154-17162. doi: 10.1074/jbc.M500843200
92. Gillardon F (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability - a point of convergence in parkinsonian neurodegeneration? J Neurochem 110:1514-1522. doi: 10.1111/j.1471-4159.2009.06235.x
93. Borland MK, Trimmer PA, Rubinstein JD et al (2008) Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells. Mol Neurodegener 3:21. doi: 10.1186/1750-1326-3-21
94. Park D-W, Nam M-K, Rhim H (2011) The serine protease HtrA2 cleaves UCH-L1 and inhibits its hydrolase activity: implication in the UCH-L1-mediated cell death. Biochem Biophys Res Commun 415:24-29. doi: 10.1016/j.bbrc.2011.09.148
95. Gusdon AM, Zhu J, Van Houten B, Chu CT (2012) ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol Dis 45:962-972. doi: 10.1016/j.nbd.2011.12.015
96. Braschi E, Goyon V, Zunino R et al (2010) Vps35 mediates vesicle transport between the mitochondria and peroxisomes. Curr Biol 20:1310-1315. doi: 10.1016/j.cub.2010.05.066
97. Chartier-Harlin M-C, Dachsel JC, Vilariño-Güell C et al (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 89:398-406. doi: 10.1016/j.ajhg.2011.08.009
98. Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441:523-540. doi: 10.1042/BJ20111451
99. Korolchuk VI, Menzies FM, Rubinsztein DC (2010) Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584:1393-1398
100. Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Molecular cell 40:280-293. doi: 10.1016/j.molcel.2010.09.023
101. Ravikumar B, Sarkar S, Davies JE et al (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383-1435. doi: 10.1152/physrev.00030.2009
102. Harris H, Rubinsztein DC (2011) Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 8:108-117. doi: 10.1038/nrneurol.2011. 200
103. Martinez-Vicente M, Talloczy Z, Kaushik S et al (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Investig 118:777-788. doi: 10.1172/JCI32806DS1
104. Nalls MA, Plagnol V, Hernandez DG 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 377:641-649
105. Grabowski GA (2008) Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 372:1263-1271
106. Yap TL, Gruschus JM, Velayati A et al (2011) {alpha}-Synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 286:28080-28088. doi: 10.1074/jbc.M111.237859
107. Westbroek W, Gustafson AM, Sidransky E (2011) Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med 17:485-493
108. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM et al (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67:1464-1472
109. Crews L, Spencer B, Desplats P et al (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5:e9313
110. Chu Y, Dodiya H, Aebischer P et al (2009) Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35:385-398. doi: 10.1016/j.nbd.2009.05.023
111. Xu M, Zhang H (2011) Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy. Acta Pharmacol Sin 32:1089-1099
112. Chu CT (2006) Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 65:423-432
113. Schapira AHV (2012) Targeting mitochondria for neuroprotection in Parkinson's disease. Antioxid Redox Signal 16:965-973. doi: 10.1089/ars.2011. 4419
114. Nixon RA, Yang D-S (2011) Autophagy failure in Alzheimer's disease - locating the primary defect. Neurobiol Dis 43:38-45. doi: 10.1016/j.nbd.2011.01. 021
115. Pickford F, Masliah E, Britschgi M et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Investig 118:2190-2199
116. Yang D-S, Stavrides P, Mohan PS et al (2011) Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis. Autophagy 7:788-789
117. Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880-884. doi: 10.1038/nature04723
118. Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885-889. doi: 10.1038/nature04724
119. Breydo L, Wu JW, Uversky VN (2012) α-Synuclein misfolding and Parkinson's disease. Biochim Biophys Acta 1822:261-285. doi: 10.1016/j.bbadis.2011.10.002
120. Ullman O, Fisher CK, Stultz CM (2011) Explaining the structural plasticity of α-synuclein. J Am Chem Soc 133:19536-19546
121. Wang W, Perovic I, Chittuluru J et al (2011) A soluble α-synuclein construct forms a dynamic tetramer. PNAS 108:17797-17802
122. Bartels T, Choi JG, Selkoe DJ (2011) α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 3-7. doi: 10.1038/nature10324
123. Lee S-J, Lim H-S, Masliah E, Lee H-J (2011) Protein aggregate spreading in neurodegenerative diseases: Problems and perspectives. Neurosci Res 70:339-348
124. Yonetani M, Nonaka T, Masuda M et al (2009) Conversion of wild-type alpha-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J Biol Chem 284:7940-7950
125. Colla E, Jensen PH, Pletnikova O et al (2012) Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci 32:3301-3305. doi: 10.1523/JNEUROSCI.5368-11.2012
126. 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 29:3365-3373. doi: 10.1523/JNEUROSCI.5427-08. 2009
127. Ihara M, Yamasaki N, Hagiwara A et al (2007) Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 53:519-533. doi: 10.1016/j.neuron.2007.01. 019
128. Kahle PJ, Neumann M, Ozmen L et al (2000) Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J Neurosci 20:6365-6373
129. Yavich L, Jäkälä P, Tanila H (2006) Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in alpha-synuclein knockout and A30P transgenic mice. J Neurochem 99:724-732. doi: 10.1111/j.1471-4159.2006.04098.x
130. Martin LJ, Pan Y, Price AC et al (2006) Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41-50. doi: 10.1523/JNEUROSCI.4308-05.2006
131. Devi L, Raghavendran V, Prabhu BM et al (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283:9089-9100. doi: 10.1074/jbc.M710012200
132. Loeb V, Yakunin E, Saada A, Sharon R (2010) The transgenic overexpression of alpha-synuclein and not its related pathology associates with complex I inhibition. J Biol Chem 285:7334-7343. doi: 10.1074/jbc.M109.061051
133. Chinta SJ, Mallajosyula JK, Rane A, Andersen JK (2010) Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett 486:235-239. doi: 10.1016/j.neulet.2010.09.061
134. Choubey V, Safiulina D, Vaarmann A et al (2011) Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem 286:10814-10824. doi: 10.1074/jbc.M110.132514
135. Esposito A, Dohm CP, Kermer P et al (2007) alpha-Synuclein and its disease-related mutants interact differentially with the microtubule protein tau and associate with the actin cytoskeleton. Neurobiol Dis 26:521-531. doi: 10.1016/j.nbd.2007.01.014
136. Lee H-J, Shin SY, Choi C et al (2002) Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277:5411-5417. doi: 10.1074/jbc.M105326200
137. Chen L, Jin J, Davis J et al (2007) Oligomeric α-synuclein inhibits tubulin polymerization. Biochem Biophys Res Commun 356:548-553. doi: 10.1016/j.bbrc.2007.02.163
138. Jensen PH (1999) alpha -Synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481-25489. doi: 10.1074/jbc.274.36.25481
139. Frasier M, Walzer M, McCarthy L et al (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 192:274-287. doi: 10.1016/j.expneurol.2004.07.016
140. Haggerty T, Credle J, Rodriguez O et al (2011) Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease. Eur J Neurosci 33:1598-1610. doi: 10.1111/j.1460-9568.2011.07660.x
141. Qureshi HY, Paudel HK (2011) Parkinsonian neurotoxin 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) and alpha-synuclein mutations promote Tau protein phosphorylation at Ser262 and destabilize microtubule cytoskeleton in vitro. J Biol Chem 286:5055-5068. doi: 10.1074/jbc.M110.178905
142. Clinton LK, Blurton-Jones M, Myczek K et al (2010) Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281-7289
143. Giasson BI, Forman MS, Higuchi M et al (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636-640. doi: 10.1126/science.1082324
144. Smith WW, Jiang H, Pei Z et al (2005) Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 14:3801-3811. doi: 10.1093/hmg/ddi396
145. Colla E, Coune P, Liu Y et al (2012) Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J Neurosci 32:3306-3320
146. Cuervo AM, Stefanis L, Fredenburg R et al (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292-1295. doi: 10.1126/science.1101738
147. Xilouri M, Vogiatzi T, Vekrellis K et al (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4:e5515. doi: 10.1371/journal.pone.0005515
148. Mazzulli JR, Xu Y-H, Sun Y et al (2011) Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37-52. doi: 10.1016/j.cell.2011.06.001
149. Tanaka Y, Engelender S, Igarashi S et al (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10:919-926. doi: 10.1093/hmg/10.9.919
150. Stefanis L, Larsen KE, Rideout HJ et al (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21:9549-9560
151. Petrucelli L, O'Farrell C, Lockhart PJ et al (2002) Parkin protects against the toxicity associated with mutant α-synuclein proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007-1019. doi: 10.1016/S0896-6273(02)01125-X
152. Lindersson E, Beedholm R, Højrup P et al (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279:12924-12934. doi: 10.1074/jbc.M306390200
153. Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33:317-325
154. Kordower JH, Chu Y, Hauser RA et al (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature Medicine 14:504-506. doi: 10.1038/nm1747
155. Kordower JH, Chu Y, Hauser RA et al (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303-2306
156. Li J-Y, Englund E, Holton JL et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Medicine 14:501-503. doi: 10.1038/nm1746
157. Desplats P, Lee H-J, Bae E-J et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. PNAS 106:13010-13015. doi: 10.1073/pnas.0903691106
158. Volpicelli-Daley LA, Luk KC, Patel TP et al (2011) Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57-71
159. Luk KC, Kehm V, Carroll J et al (2012) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949-953. doi: 10.1126/science.1227157
160. Jang A, Lee H-J, Suk J-E et al (2010) Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113:1263-1274
161. Lee H-J, Patel S, Lee S-J (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25:6016-6024
162. Luk KC, Song C, O'Brien P et al (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. PNAS 106:20051-20056
163. Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE (2012) Inflammation and adaptive immunity in Parkinson's disease. Cold Spring Harbor perspectives in medicine 2:a009381.
164. McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24:574-576
165. Brochard V, Combadière B, Prigent A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Investig 119:182-192. doi: 10.1172/JCI36470
166. Double KL, Rowe DB, Carew-Jones FM et al (2009) Anti-melanin antibodies are increased in sera in Parkinson's disease. Exp Neurol 217:297-301. doi: 10.1016/j.expneurol.2009.03.002
167. Reynolds AD, Stone DK, Hutter J a L et al (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 184:2261-2271. doi: 10.4049/jimmunol. 0901852, Baltimore, Md: 1950
168. Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110-122
169. Glass CK, Saijo K, Winner B et al (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918-934. doi: 10.1016/j.cell.2010. 02.016
170. Rocha SM, Cristovão AC, Campos FL et al (2012) Astrocyte-derived GDNF is a potent inhibitor of microglial activation. Neurobiol Dis 47:407-415. doi: 10.1016/j.nbd.2012.04.014
171. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314-1318
172. Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752-758
173. Mott RT, Ait-Ghezala G, Town T et al (2004) Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 46:369-379
174. Majed HH, Chandran S, Niclou SP et al (2006) A novel role for Sema3A in neuroprotection from injury mediated by activated microglia. J Neurosci 26:1730-1738
175. Tian L, Rauvala H, Gahmberg CG (2009) Neuronal regulation of immune responses in the central nervous system. Trends Immunol 30:91-99
176. Koning N, Bö L, Hoek RM, Huitinga I (2007) Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol 62:504-514
177. Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917-924
178. Kim WG, Mohney RP, Wilson B et al (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci: Off J Soc Neurosci 20:6309-6316
179. Mena M a, Yébenes G d J (2008) Immune activation in brain aging and neurodegeneration: too much or too little? Neuroscientist 14:544-560. doi: 10.1177/1073858408322839
180. Zecca L, Wilms H, Geick S et al (2008) Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. Acta Neuropathol 116:47-55. doi: 10.1007/s00401-008-0361-7
181. 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 38:1285-1285
182. Langston JW, Forno LS, Tetrud J et al (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598-605
183. McGeer PL, Schwab C, Parent A, Doudet D (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine administration. Ann Neurol 54:599-604. doi: 10.1002/ana.10728
184. Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) induced Parkinson's disease mice model. Neurodegeneration 5:137-143
185. Walsh S, Finn DP, Dowd E (2011) Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 175:251-261. doi: 10.1016/j.neuroscience.2010.12.005
186. Gao H, Liu B, Zhang W, Hong J (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson's disease. FASEB J 17:1954-1956. doi: 10.1096/fj.03-0109fje
187. Zhang W, Wang T, Pei Z et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 19:533-542. doi: 10.1096/fj.04-2751com
188. Béraud D, Twomey M, Bloom B et al (2011) α-Synuclein alters Toll-like receptor expression. Frontiers in. Neuroscience 5:80
189. Zhang W, Dallas S, Zhang D et al (2007) Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. Glia 55:1178-1188
190. Alvarez-Erviti L, Couch Y, Richardson J et al (2011) Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci Res 69:337-342. doi: 10.1016/j.neures.2010.12.020
191. 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 208:41-48. doi: 10.1016/j.neuroscience.2012.02.001
192. Frank-Cannon TC, Tran T, Ruhn K a et al (2008) Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci 28:10825-10834. doi: 10.1523/JNEUROSCI.3001-08.2008
193. Waak J, Weber SS, Waldenmaier A et al (2009) Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1. FASEB J 23:2478-2489. doi: 10.1096/fj.08-125153
194. Wu DC, Jackson-Lewis V, Vila M 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 22:1763-1771
195. Perier C, Bové J, Vila M (2012) Mitochondria and programmed cell death in Parkinson's disease: apoptosis and beyond. Antioxid Redox Signal 16:883-895. doi: 10.1089/ars.2011.4074
196. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47-59. doi: 10.1038/nrm2308
197. Tait SWG, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621-632. doi: 10.1038/nrm2952
198. Offen D, Beart PM, Cheung NS et al (1998) Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity. PNAS 95:5789-5794
199. Yang L, Matthews RT, Schulz JB et al (1998) 1-Methyl-4-phenyl-1,2,3,6- tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2. J Neurosci 18:8145-8152
200. Vila M, Jackson-Lewis V, Vukosavic S et al (2001) Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6- tetrahydropyridine mouse model of Parkinson's disease. PNAS 98:2837-2842. doi: 10.1073/pnas.051633998
201. Perier C, Bové J, Wu D-C et al (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease. PNAS 104:8161-8166. doi: 10.1073/pnas.0609874104
202. Dietz GPH, Stockhausen KV, Dietz B et al (2008) Membrane-permeable Bcl-xL prevents MPTP-induced dopaminergic neuronal loss in the substantia nigra. J Neurochem 104:757-765. doi: 10.1111/j.1471-4159.2007.05028.x
203. Iaccarino C, Crosio C, Vitale C et al (2007) Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 16:1319-1326. doi: 10.1093/hmg/ddm080
204. Darios F, Corti O, Lücking CB et al (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12:517-526
205. Petit A, Kawarai T, Paitel E et al (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 280:34025-34032. doi: 10.1074/jbc.M505143200
206. Wang H-L, Chou A-H, Yeh T-H et al (2007) PINK1 mutants associated with recessive Parkinson's disease are defective in inhibiting mitochondrial release of cytochrome c. Neurobiol Dis 28:216-226. doi: 10.1016/j.nbd.2007.07.010
207. Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27:6434-6451. doi: 10.1038/onc.2008.310
208. Turk B, Turk DSA, Turk V (2012) Protease signalling: the cutting edge. EMBO J 31:1630-1643. doi: 10.1038/emboj.2012.42
209. Jeon S-M, Cheon S-M, Bae H-R et al (2010) Selective susceptibility of human dopaminergic neural stem cells to dopamine-induced apoptosis. Exp Neurobiol 19:155-164. doi: 10.5607/en.2010.19.3.155
210. Benner EJ, Banerjee R, Reynolds AD et al (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376. doi: 10.1371/journal.pone.0001376
211. Gao H-M, Zhou H, Zhang F et al (2011) HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci 31:1081-1092. doi: 10.1523/JNEUROSCI.3732-10.2011
212. Simi A, Tsakiri N, Wang P, Rothwell NJ (2007) Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans 35:1122-1126
213. McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45. doi: 10.1186/1742-2094-5-45
214. Magrane M, Consortium U (2011) UniProt Knowledgebase: a hub of integrated protein data. Database (Oxford) 2011:bar009.
215. Seal RL, Gordon SM, Lush MJ et al (2011) genenames.org: the HGNC resources in 2011. Nucleic Acids Res 39:D514-D519
216. Cochrane G, Akhtar R, Bonfield J et al (2009) Petabyte-scale innovations at the European Nucleotide Archive. Nucleic Acids Res 37:19-25
217. Flicek P, Amode MR, Barrell D et al (2012) Ensembl 2012. Nucleic Acids Res 40:84-90
218. Fujita PA, Rhead B, Zweig AS et al (2011) The UCSC Genome Browser database: update 2011. Nucleic Acids Res 39:D876-D882
219. Pruitt KD, Tatusova T, Brown GR, Maglott DR (2012) NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy. Nucleic Acids Res 40:D130-D135
220. Maglott D, Ostell J, Pruitt KD, Tatusova T (2011) Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res 39:D52-D57
221. Schuler GD (1997) Pieces of the puzzle: expressed sequence tags and the catalog of human genes. J Mol Med 75:694-698
222. Safran M, Dalah I, Alexander J, et al. (2010) Gene Cards Version 3: the human gene integrator. Database (Oxford) 2010:baq020.
223. Berman H, Henrick K, Nakamura H, Markley JL (2007) The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data. Nucleic Acids Res 35:D301-D303
224. Ashburner M, Ball CA, Blake JA et al (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25-29
225. Kanehisa M, Goto S, Sato Y et al (2012) KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40:D109-D114
226. Mi H, Lazareva-Ulitsky B, Loo R et al (2005) The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res 33:D284-D288
227. Croft D, O'Kelly G, Wu G et al (2011) Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res 39:D691-D697
228. Punta M, Coggill PC, Eberhardt RY et al (2012) The Pfam protein families database. Nucleic Acids Res 40:290-301
229. Hunter S, Jones P, Mitchell A et al (2012) InterPro in 2011: new developments in the family and domain prediction database. Nucleic Acids Res 40:D306-D312
230. cDonagh EM, Whirl-Carrillo M, Garten Y et al (2011) From pharmacogenomic knowledge acquisition to clinical applications: the PharmGKB as a clinical pharmacogenomic biomarker resource. Biomark Med 5:795-806
231. Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson's disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet 137B:5-16. doi: 10.1002/ajmg.b.30195
232. Lesnick TG, Papapetropoulos S, Mash DC et al (2007) A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet 3:12
233. Moran LB, Duke DC, Deprez M et al (2006) Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease. Neurogenetics 7:1-11
234. Zheng B, Liao Z, Locascio JJ et al (2010) PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med 2:52ra-73ra
235. Scherzer CR, Eklund AC, Morse LJ et al (2007) Molecular markers of early Parkinson's disease based on gene expression in blood. PNAS 104:955-960
236. Sforza D, Hartenstein P, Lacan G, et al. (2008) Gene expression changes in multiple brain regions of a mouse MPTP model of Parkinson's disease. Fairfax, VA 22030 USA
237. Foti R, Zucchelli S, Biagioli M et al (2010) Parkinson disease-associated DJ-1 is required for the expression of the glial cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells. J Biol Chem 285:18565-18574
238. Rajagopalan D, Agarwal P (2005) Inferring pathways from gene lists using a literature-derived network of biological relationships. Bioinformatics 21:788-793. doi: 10.1093/bioinformatics/bti069
239. Ulitsky I, Shamir R (2009) Identifying functional modules using expression profiles and confidence-scored protein interactions. Bioinformatics 25:1158-1164. doi: 10.1093/bioinformatics/btp118
240. Cerami E, Demir E, Schultz N et al (2010) Automated network analysis identifies core pathways in glioblastoma. PLoS One 5:e8918. doi: 10.1371/journal.pone.0008918
241. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. PNAS 98:5116-5121. doi: 10.1073/pnas.091062498
242. Aerts S, Lambrechts D, Maity S et al (2006) Gene prioritization through genomic data fusion. Nat Biotechnol 24:537-544. doi: 10.1038/nbt1203
243. Ma X, Lee H, Wang L, Sun F (2007) CGI: a new approach for prioritizing genes by combining gene expression and protein-protein interaction data. Bioinformatics 23:215-221. doi: 10.1093/bioinformatics/btl569
244. Zaykin DV, Zhivotovsky LA, Czika W et al (2007) Combining p-values in large-scale genomics experiments. Pharm Stat 6:217-226. doi: 10.1002/pst.304
245. Marot G, Foulley J-L, Mayer C-D, Jaffrézic F (2009) Moderated effect size and P-value combinations for microarray meta-analyses. Bioinformatics 25:2692-2699
246. Aittokallio T, Schwikowski B (2006) Graph-based methods for analysing networks in cell biology. Brief Bioinform 7:243-255. doi: 10.1093/bib/bbl022
247. Emmert-Streib F, Dehmer M (2011) Networks for systems biology: conceptual connection of data and function. IET Syst Biol 5:185. doi: 10.1049/iet-syb. 2010.0025
248. Junker BH, Schreiber F (2008) Analysis of biological networks. Science 1-28. doi: 10.1002/9780470253489
249. Guimerà R, Sales-Pardo M, Amaral LAN (2007) Classes of complex networks defined by role-to-role connectivity profiles. Nat Phys 3:63-69. doi: 10.1038/nphys489
250. Wang R-S, Albert R (2011) Elementary signaling modes predict the essentiality of signal transduction network components. BMC Syst Biol 5:44
251. Klipp E, Liebermeister W (2006) Mathematical modeling of intracellular signaling pathways. BMC Neurosci 7(Suppl 1):S10. doi: 10.1186/1471-2202-7-S1-S10
252. Hucka M, Finney a, Sauro HM (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:524-531. doi: 10.1093/bioinformatics/btg015
253. Hoops S, Sahle S, Gauges R et al (2006) COPASI - a COmplex PAthway SImulator. Bioinform (Oxford, England) 22:3067-3074. doi: 10.1093/ bioinformatics/btl485
254. Van Eunen K, Kiewiet J a L, Westerhoff HV, Bakker BM (2012) Testing biochemistry revisited: how in vivo metabolism can be understood from in vitro enzyme kinetics. PLoS Comput Biol 8:e1002483. doi: 10.1371/journal.pcbi.1002483
255. Kowald A, Hamann A, Zintel S et al (2012) A systems biological analysis links ROS metabolism to mitochondrial protein quality control. MechAgeing Dev 133:331-337. doi: 10.1016/j.mad.2012.03.008
256. Berndt N, Bulik S, Holzhütter H-G (2012) Kinetic modeling of the mitochondrial energy metabolism of neuronal cells: the impact of reduced α-ketoglutarate dehydrogenase activities on ATP production and generation of reactive oxygen species. International journal of cell biology 2012:757594. doi: 10.1155/2012/757594
257. Craddock TJ a, Tuszynski J a, Chopra D et al (2012) The zinc dyshomeostasis hypothesis of Alzheimer's disease. PLoS One 7:e33552. doi: 10.1371/journal.pone.0033552
258. Ambert N, Greget R, Haeberlé O et al (2010) Computational studies of NMDA receptors: differential effects of neuronal activity on efficacy of competitive and non-competitive antagonists. Open Access Bioinforma 2:113-125. doi: 10.2147/OAB.S7246
259. Berardini TZ, Li D, Muller R, et al. (2012) Assessment of community-submitted ontology annotations from a novel database-journal partnership. Databaseâ€̄: the journal of biological databases and curation 2012:bas030. doi: 10.1093/database/bas030
260. Meyer P, Alexopoulos LG, Bonk T et al (2011) Verification of systems biology research in the age of collaborative competition. Nat Biotechnol 29:811-815. doi: 10.1038/nbt.1968
261. Meyer P, Hoeng J, Rice JJ et al (2012) Industrial methodology for process verification in research (IMPROVER): toward systems biology verification. Bioinform (Oxford, England) 28:1193-1201. doi: 10.1093/bioinformatics/bts116
262. Nielsen MA (2011) Reinventing discovery: the new era of networked science. Princeton University Press, Princeton, NJ
263. Kelder T, Van Iersel MP, Hanspers K et al (2012) WikiPathways: building research communities on biological pathways. Nucleic Acids Res 40:D1301-D1307. doi: 10.1093/nar/gkr1074
264. Matsuoka Y, Ghosh S, Kikuchi N, Kitano H (2010) Payao: a community platform for SBML pathway model curation. Bioinformatics 26:1381-1383. doi: 10.1093/bioinformatics/btq143
265. Le Novère N, Hucka M, Mi H et al (2009) The systems biology graphical notation. Nat Biotechnol 27:735-741