α-synuclein oligomers and clinical implications for parkinson disease

Annals of Neurology

Volumn 73, Issue 2, 2013, Pages 155-169

  Kalia, Lorraine V ^a,b   Kalia, Suneil K ^b   McLean, Pamela J ^c   Lozano, Andres M ^b   Lang, Anthony E ^a,b  

^a TORONTO WESTERN HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; BIOLOGICAL MARKER; MONOMER; OLIGOMER; POLYQ PROTEIN; PRION PROTEIN; TAR DNA BINDING PROTEIN; TAU PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; CELL DEATH; HUMAN; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL;

ALPHA-SYNUCLEIN; ANIMALS; HUMANS; INCLUSION BODIES; NERVE DEGENERATION; OLIGONUCLEOTIDES; PARKINSON DISEASE;

EID: 84875415994     PISSN: 03645134     EISSN: 15318249     Source Type: Journal    
DOI: 10.1002/ana.23746     Document Type: Article

References (170)

1. Lewy F,. Paralysis agitans. In:, Lewandowski M, ed. Handbuch der Neurologie. Berlin, Germany: Springer, 1912: 920-933.
2. Ueda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 1993; 90: 11282-11286.
3. Jakes R, Spillantini MG, Goedert M,. Identification of two distinct synucleins from human brain. FEBS Lett 1994; 345: 27-32.
4. Wang W, Perovic I, Chittuluru J, et al. A soluble alpha-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 2011; 108: 17797-17802.
5. Bartels T, Choi JG, Selkoe DJ,. alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011; 477: 107-110.
6. Chandra S, Gallardo G, Fernandez-Chacon R, et al. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005; 123: 383-396.
7. Fauvet B, Mbefo MK, Fares MB, et al. alpha-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem 2012; 287: 15345-15364.
8. Eichner T, Radford SE,. A diversity of assembly mechanisms of a generic amyloid fold. Mol Cell 2011; 43: 8-18.
9. Walsh DM, Lomakin A, Benedek GB, et al. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem 1997; 272: 22364-22372.
10. Conway KA, Harper JD, Lansbury PT,. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 1998; 4: 1318-1320.
11. Lashuel HA, Petre BM, Wall J, et al. Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 2002; 322: 1089-1102.
12. Harper JD, Lieber CM, Lansbury PT Jr,. Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-beta protein. Chem Biol 1997; 4: 951-959.
13. Wacker JL, Zareie MH, Fong H, et al. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 2004; 11: 1215-1222.
14. Hu CD, Chinenov Y, Kerppola TK,. Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 2002; 9: 789-798.
15. Outeiro TF, Putcha P, Tetzlaff JE, et al. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 2008; 3: e1867.
16. Tetzlaff JE, Putcha P, Outeiro TF, et al. CHIP targets toxic alpha-synuclein oligomers for degradation. J Biol Chem 2008; 283: 17962-17968.
17. Putcha P, Danzer KM, Kranich LR, et al. Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity. J Pharmacol Exp Ther 2010; 332: 849-857.
18. Kalia LV, Kalia SK, Chau H, et al. Ubiquitinylation of alpha-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 2011; 6: e14695.
19. Danzer KM, Ruf WP, Putcha P, et al. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J 2011; 25: 326-336.
20. Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011; 146: 37-52.
21. Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011; 108: 4194-4199.
22. Sharon R, Bar-Joseph I, Frosch MP, et al. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron 2003; 37: 583-595.
23. El-Agnaf OM, Salem SA, Paleologou KE, et al. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 2006; 20: 419-425.
24. Tokuda T, Qureshi MM, Ardah MT, et al. Detection of elevated levels of alpha-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 2010; 75: 1766-1772.
25. Ross CA, Poirier MA,. Protein aggregation and neurodegenerative disease. Nat Med 2004; 10 (suppl): S10-S17.
26. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839-840.
27. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045-2047.
28. Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998; 18: 106-108.
29. Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55: 164-173.
30. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 2005; 280: 7800-7807.
31. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science 2003; 302: 841.
32. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004; 364: 1167-1169.
33. Minton AP,. Influence of macromolecular crowding upon the stability and state of association of proteins: predictions and observations. J Pharm Sci 2005; 94: 1668-1675.
34. Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009; 41: 1303-1307.
35. Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41: 1308-1312.
36. Fuchs J, Tichopad A, Golub Y, et al. Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB J 2008; 22: 1327-1334.
37. Mata IF, Shi M, Agarwal P, et al. SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 2010; 67: 1350-1356.
38. Neumann M, Kahle PJ, Giasson BI, et al. Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 2002; 110: 1429-1439.
39. Fujiwara H, Hasegawa M, Dohmae N, et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002; 4: 160-164.
40. Yamin G, Uversky VN, Fink AL,. Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. FEBS Lett 2003; 542: 147-152.
41. Hartl FU, Bracher A, Hayer-Hartl M,. Molecular chaperones in protein folding and proteostasis. Nature 2011; 475: 324-332.
42. Tyedmers J, Mogk A, Bukau B,. Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol 2010; 11: 777-788.
43. Cook C, Petrucelli L,. A critical evaluation of the ubiquitin-proteasome system in Parkinson's disease. Biochim Biophys Acta 2009; 1792: 664-675.
44. Chu Y, Dodiya H, Aebischer P, et al. Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 2009; 35: 385-398.
45. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 2010; 67: 1464-1472.
46. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009; 361: 1651-1661.
47. Calne DB, Langston JW,. Aetiology of Parkinson's disease. Lancet 1983; 2: 1457-1459.
48. Collier TJ, Kanaan NM, Kordower JH,. Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 2011; 12: 359-366.
49. Kourtis N, Tavernarakis N,. Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 2011; 30: 2520-2531.
50. Braak H, Del TK, Rub U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24: 197-211.
51. Cookson MR, Hardy J, Lewis PA,. Genetic neuropathology of Parkinson's disease. Int J Clin Exp Pathol 2008; 1: 217-231.
52. Forno LS,. Concentric hyalin intraneuronal inclusions of Lewy type in the brains of elderly persons (50 incidental cases): relationship to parkinsonism. J Am Geriatr Soc 1969; 17: 557-575.
53. Saito Y, Ruberu NN, Sawabe M, et al. Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol 2004; 63: 742-749.
54. Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 2001; 50: 293-300.
55. Pramstaller PP, Schlossmacher MG, Jacques TS, et al. Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 2005; 58: 411-422.
56. Sasaki S, Shirata A, Yamane K, et al. Parkin-positive autosomal recessive juvenile Parkinsonism with alpha-synuclein-positive inclusions. Neurology 2004; 63: 678-682.
57. Matsumine H, Saito M, Shimoda-Matsubayashi S, et al. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. Am J Hum Genet 1997; 60: 588-596.
58. Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 1998; 51: 890-892.
59. Yamamura Y, Kuzuhara S, Kondo K, et al. Clinical, pathologic and genetic studies on autosomal recessive early-onset parkinsonism with diurnal fluctuation. Parkinsonism Relat Disord 1998; 4: 65-72.
60. Yamamura Y, Hattori N, Matsumine H, et al. Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification. Brain Dev 2000; 22 (suppl 1): S87-S91.
61. Hayashi S, Wakabayashi K, Ishikawa A, et al. An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 2000; 15: 884-888.
62. van de Warrenburg BP, Lammens M, Lucking CB, et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 2001; 56: 555-557.
63. Gouider-Khouja N, Larnaout A, Amouri R, et al. Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study. Parkinsonism Relat Disord 2003; 9: 247-251.
64. Corti O, Lesage S, Brice A,. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev 2011; 91: 1161-1218.
65. Gilks WP, Abou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005; 365: 415-416.
66. Khan NL, Jain S, Lynch JM, et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005; 128: 2786-2796.
67. Giasson BI, Covy JP, Bonini NM, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006; 59: 315-322.
68. Rajput A, Dickson DW, Robinson CA, et al. Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006; 67: 1506-1508.
69. Ross OA, Toft M, Whittle AJ, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006; 59: 388-393.
70. Gaig C, Marti MJ, Ezquerra M, et al. G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. J Neurol Neurosurg Psychiatry 2007; 78: 626-628.
71. Giordana MT, D'Agostino C, Albani G, et al. Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Val mutation. Mov Disord 2007; 22: 275-278.
72. Gaig C, Ezquerra M, Marti MJ, et al. Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration. J Neurol Sci 2008; 270: 94-98.
73. Covy JP, Yuan W, Waxman EA, et al. Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Mov Disord 2009; 24: 32-39.
74. Gaig C, Marti MJ, Ezquerra M, et al. G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. J Neurol Neurosurg Psychiatry 2007; 78: 626-628.
75. Hasegawa K, Stoessl AJ, Yokoyama T, et al. Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat Disord 2009; 15: 300-306.
76. Marti-Masso JF, Ruiz-Martinez J, Bolano MJ, et al. Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2. Mov Disord 2009; 24: 1998-2001.
77. Gomez A, Ferrer I,. Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment. Acta Neuropathol 2010; 120: 155-167.
78. Kingsbury AE, Bandopadhyay R, Silveira-Moriyama L, et al. Brain stem pathology in Parkinson's disease: an evaluation of the Braak staging model. Mov Disord 2010; 25: 2508-2515.
79. Vitte J, Traver S, Maues De Paula A, et al. Leucine-rich repeat kinase 2 is associated with the endoplasmic reticulum in dopaminergic neurons and accumulates in the core of Lewy bodies in Parkinson disease. J Neuropathol Exp Neurol 2010; 69: 959-972.
80. Poulopoulos M, Cortes E, Vonsattel JP, et al. Clinical and pathological characteristics of LRRK2 G2019S patients with PD. J Mol Neurosci 2011; 47: 139-143.
81. Bezard E, Przedborski S,. A tale on animal models of Parkinson's disease. Mov Disord 2011; 26: 993-1002.
82. Dauer W, Kholodilov N, Vila M, et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A 2002; 99: 14524-14529.
83. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000; 3: 1301-1306.
84. Maries E, Dass B, Collier TJ, et al. The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci 2003; 4: 727-738.
85. Dawson TM, Ko HS, Dawson VL,. Genetic animal models of Parkinson's disease. Neuron 2010; 66: 646-661.
86. Lee MK, Stirling W, Xu Y, et al. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 - > Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 2002; 99: 8968-8973.
87. Giasson BI, Duda JE, Quinn SM, et al. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002; 34: 521-533.
88. Karpinar DP, Balija MB, Kugler S, et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. EMBO J 2009; 28: 3256-3268.
89. Lim SY, Fox SH, Lang AE,. Overview of the extranigral aspects of Parkinson disease. Arch Neurol 2009; 66: 167-172.
90. Tsika E, Moysidou M, Guo J, et al. Distinct region-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration. J Neurosci 2010; 30: 3409-3418.
91. Paleologou KE, Kragh CL, Mann DM, et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 2009; 132: 1093-1101.
92. Tayebi N, Walker J, Stubblefield B, et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 2003; 79: 104-109.
93. Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004; 82: 192-207.
94. Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 2009; 132: 1783-1794.
95. Goker-Alpan O, Stubblefield BK, Giasson BI, et al. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol 2010; 120: 641-649.
96. Nishioka K, Ross OA, Vilarino-Guell C, et al. Glucocerebrosidase mutations in diffuse Lewy body disease. Parkinsonism Relat Disord 2011; 17: 55-57.
97. Hinault MP, Cuendet AF, Mattoo RU, et al. Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. J Biol Chem 2010; 285: 38173-38182.
98. Petrucelli L, O'Farrell C, Lockhart PJ, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 2002; 36: 1007-1019.
99. Kalia SK, Lee S, Smith PD, et al. BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron 2004; 44: 931-945.
100. Lindersson E, Beedholm R, Hojrup P, et al. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 2004; 279: 12924-12934.
101. Ron D, Walter P,. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519-529.
102. Smith WW, Jiang H, Pei Z, et al. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 2005; 14: 3801-3811.
103. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 2006; 313: 324-328.
104. Colla E, Jensen PH, Pletnikova O, et al. Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo. J Neurosci 2012; 32: 3301-3305.
105. Colla E, Coune P, Liu Y, et al. Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci 2012; 32: 3306-3320.
106. Volles MJ, Lee SJ, Rochet JC, et al. Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry 2001; 40: 7812-7819.
107. Danzer KM, Haasen D, Karow AR, et al. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 2007; 27: 9220-9232.
108. Huls S, Hogen T, Vassallo N, et al. AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced alpha-synuclein oligomers. J Neurochem 2011; 117: 868-878.
109. Martin ZS, Neugebauer V, Dineley KT, et al. alpha-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases. J Neurochem 2012; 120: 440-452.
110. Jucker M, Walker LC,. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 2011; 70: 532-540.
111. Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 2008; 14: 504-506.
112. Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 2008; 14: 501-503.
113. Kordower JH, Dodiya HB, Kordower AM, et al. Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 2011; 43: 552-557.
114. Hansen C, Angot E, Bergstrom AL, et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 2011; 121: 715-725.
115. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011; 72: 57-71.
116. Liu J, Zhang JP, Shi M, et al. Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein. J Neurosci 2009; 29: 1480-1485.
117. Emmanouilidou E, Melachroinou K, Roumeliotis T, et al. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010; 30: 6838-6851.
118. Lee HJ, Suk JE, Bae EJ, et al. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 2008; 40: 1835-1849.
119. Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 2009; 106: 13010-13015.
120. Angot E, Steiner JA, Hansen C, et al. Are synucleinopathies prion-like disorders? Lancet Neurol 2010; 9: 1128-1138.
121. Goedert M, Clavaguera F, Tolnay M,. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 2010; 33: 317-325.
122. Cremades N, Cohen SI, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of alpha-synuclein. Cell 2012; 149: 1048-1059.
123. Lang AE, Lozano AM,. Parkinson's disease. First of two parts. N Engl J Med 1998; 339: 1044-1053.
124. Hughes AJ, Daniel SE, Lees AJ,. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology 2001; 57: 1497-1499.
125. Fearnley JM, Lees AJ,. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991; 114: 2283-2301.
126. Gibb WR, Lees AJ,. The significance of the Lewy body in the diagnosis of idiopathic Parkinson's disease. Neuropathol Appl Neurobiol 1989; 15: 27-44.
127. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann Neurol 2004; 55: 306-319.
128. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305: 275-283.
129. Hefti F,. PET Radiopharmaceuticals for detection and differential diagnosis of Parkinson's disease. Paper presented at: Harvard NeuroDiscovery Center Annual Symposium. Progress in Molecular Neurology: A Parkinson's Disease Perspective; November 16, 2009; Boston, MA.
130. Kikuchi A, Takeda A, Okamura N, et al. In vivo visualization of alpha-synuclein deposition by carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5- yl)ethenyl]-6-[2-(fluoro)ethoxy]benzoxazole positron emission tomography in multiple system atrophy. Brain 2010; 133: 1772-1778.
131. Cohen P, Tcherpakov M,. Will the ubiquitin system furnish as many drug targets as protein kinases? Cell 2010; 143: 686-693.
132. Sato H, Arawaka S, Hara S, et al. Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease. J Neurosci 2011; 31: 16884-16894.
133. Ahmad B, Lapidus LJ,. Curcumin prevents aggregation in alpha-synuclein by increasing reconfiguration rate. J Biol Chem 2012; 287: 9193-9199.
134. Caruana M, Hogen T, Levin J, et al. Inhibition and disaggregation of alpha-synuclein oligomers by natural polyphenolic compounds. FEBS Lett 2011; 585: 1113-1120.
135. El-Agnaf OM, Paleologou KE, Greer B, et al. A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB J 2004; 18: 1315-1317.
136. Nasstrom T, Goncalves S, Sahlin C, et al. Antibodies against alpha-synuclein reduce oligomerization in living cells. PLoS One 2011; 6: e27230.
137. Emadi S, Barkhordarian H, Wang MS, et al. Isolation of a human single chain antibody fragment against oligomeric alpha-synuclein that inhibits aggregation and prevents alpha-synuclein-induced toxicity. J Mol Biol 2007; 368: 1132-1144.
138. Emadi S, Kasturirangan S, Wang MS, et al. Detecting morphologically distinct oligomeric forms of alpha-synuclein. J Biol Chem 2009; 284: 11048-11058.
139. Masliah E, Rockenstein E, Adame A, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 2005; 46: 857-868.
140. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 2011; 6: e19338.
141. Wisniewski T, Konietzko U,. Amyloid-beta immunisation for Alzheimer's disease. Lancet Neurol 2008; 7: 805-811.
142. Kalia SK, Kalia LV, McLean PJ,. Molecular chaperones as rational drug targets for Parkinson's disease therapeutics. CNS Neurol Disord Drug Targets 2010; 9: 741-753.
143. Lee HJ, Khoshaghideh F, Patel S, et al. Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 2004; 24: 1888-1896.
144. Lu JH, Tan JQ, Durairajan SS, et al. Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy. Autophagy 2012; 8: 98-108.
145. Olanow CW, McNaught KS,. Ubiquitin-proteasome system and Parkinson's disease. Mov Disord 2006; 21: 1806-1823.
146. Halliday GM, Stevens CH,. Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 2011; 26: 6-17.
147. Zhu Y, Hou H, Rezai-Zadeh K, et al. CD45 deficiency drives amyloid-beta peptide oligomers and neuronal loss in Alzheimer's disease mice. J Neurosci 2011; 31: 1355-1365.
148. Benilova I, Karran E, De SB,. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 2012; 15: 349-357.
149. Pike CJ, Walencewicz AJ, Glabe CG, et al. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 1991; 563: 311-314.
150. Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535-539.
151. McLean CA, Cherny RA, Fraser FW, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999; 46: 860-866.
152. Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, et al. Preparation and characterization of neurotoxic tau oligomers. Biochemistry 2010; 49: 10039-10041.
153. Chun W, Waldo GS, Johnson GV,. Split GFP complementation assay for quantitative measurement of tau aggregation in situ. Methods Mol Biol 2011; 670: 109-123.
154. Berger Z, Roder H, Hanna A, et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 2007; 27: 3650-3662.
155. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, et al. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener 2011; 6: 39.
156. Maeda S, Sahara N, Saito Y, et al. Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease. Neurosci Res 2006; 54: 197-201.
157. Maeda S, Sahara N, Saito Y, et al. Granular tau oligomers as intermediates of tau filaments. Biochemistry 2007; 46: 3856-3861.
158. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, et al. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J 2012; 26: 1946-1959.
159. Silveira JR, Raymond GJ, Hughson AG, et al. The most infectious prion protein particles. Nature 2005; 437: 257-261.
160. Biasini E, Turnbaugh JA, Unterberger U, et al. Prion protein at the crossroads of physiology and disease. Trends Neurosci 2012; 35: 92-103.
161. Simoneau S, Rezaei H, Sales N, et al. In vitro and in vivo neurotoxicity of prion protein oligomers. PLoS Pathog 2007; 3: e125.
162. Minaki H, Sasaki K, Honda H, et al. Prion protein oligomers in Creutzfeldt-Jakob disease detected by gel-filtration centrifuge columns. Neuropathology 2009; 29: 536-542.
163. Schaffar G, Breuer P, Boteva R, et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 2004; 15: 95-105.
164. Lajoie P, Snapp EL,. Formation and toxicity of soluble polyglutamine oligomers in living cells. PLoS One 2010; 5: e15245.
165. Sathasivam K, Lane A, Legleiter J, et al. Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington's disease. Hum Mol Genet 2010; 19: 65-78.
166. Legleiter J, Mitchell E, Lotz GP, et al. Mutant huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J Biol Chem 2010; 285: 14777-14790.
167. Shirendeb U, Reddy AP, Manczak M, et al. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Hum Mol Genet 2011; 20: 1438-1455.
168. Takahashi T, Kikuchi S, Katada S, et al. Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum Mol Genet 2008; 17: 345-356.
169. Jochum T, Ritz ME, Schuster C, et al. Toxic and non-toxic aggregates from the SBMA and normal forms of androgen receptor have distinct oligomeric structures. Biochim Biophys Acta 2012; 1822: 1070-1078.
170. Li M, Chevalier-Larsen ES, Merry DE, et al. Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J Biol Chem 2007; 282: 3157-3164.