α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease

Annals of Clinical and Translational Neurology

Volumn 3, Issue 8, 2016, Pages 588-606

  Spencer, Brian ^a   Williams, Stephanie ^b   Rockenstein, Edward ^a   Valera, Elvira ^a   Xin, Wei ^b   Mante, Michael ^a   Florio, Jazmin ^a   Adame, Anthony ^a   Masliah, Eliezer ^a,c   Sierks, Michael R ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Arizona State University   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; LENTIVIRUS VECTOR; PENETRATIN; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD BRAIN BARRIER; CELL CULTURE; CONTROLLED STUDY; DIFFUSE LEWY BODY DISEASE; ENZYME LINKED IMMUNOSORBENT ASSAY; IMMUNOCYTOCHEMISTRY; IMMUNOHISTOCHEMISTRY; MALE; MOUSE; NERVE DEGENERATION; NEUROBLASTOMA CELL LINE; NEUROPATHOLOGY; NEUROPIL; NONHUMAN; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; RAT;

EID: 85010435546     PISSN: None     EISSN: 23289503     Source Type: Journal    
DOI: 10.1002/acn3.321     Document Type: Article

References (72)

1. Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998;44:415–422.
2. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 1998;249:180–182.
3. Baba M, Nakajo S, Tu PH, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 1998;152:879–884.
4. Spillantini MG, Crowther RA, Jakes R, et al. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 1998;251:205–208.
5. 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.
6. Dickson DW, Liu W, Hardy J, et al. Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 1999;155:1241–1251.
7. Periquet M, Fulga T, Myllykangas L, et al. Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci 2007;27:3338–3346.
8. 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.
9. Diogenes MJ, Dias RB, Rombo DM, et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci 2012;32:11750–11762.
10. 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.
11. Outeiro TF, Putcha P, Tetzlaff JE, et al. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 2008;3:e1867.
12. 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.
13. Yuan B, Sierks MR. Intracellular targeting and clearance of oligomeric alpha-synuclein alleviates toxicity in mammalian cells. Neurosci Lett 2009;459:16–18.
14. Tofaris GK, Spillantini MG. Physiological and pathological properties of alpha-synuclein. Cell Mol Life Sci 2007;64:2194–2201.
15. Spencer B, Emadi S, Desplats P, et al. ESCRT mediated uptake and degradation of brain targeted α-synuclein-single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 2014;22:1753–1767.
16. Valera E, Masliah E. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol Ther 2013;138:311–322.
17. Valera E, Spencer B, Masliah E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 2015;1:179–189.
18. Lindstrom V, Fagerqvist T, Nordstrom E, et al. Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice. Neurobiol Dis 2014;69:134–143.
19. Lynch SM, Zhou C, Messer A. An scFv intrabody against the nonamyloid component of alpha-synuclein reduces intracellular aggregation and toxicity. J Mol Biol 2008;377:136–147.
20. 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.
21. Mandler M, Valera E, Rockenstein E, et al. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 2015;10:10.
22. Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol 2014;127:861–879.
23. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci 2012;32:13454–13469.
24. Games D, Valera E, Spencer B, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci 2014;34:9441–9454.
25. 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.
26. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human alpha-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson's disease. PLoS One 2015;10:e0116841.
27. Tran HT, Chung CH, Iba M, et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep 2014;7:2054–2065.
28. Ahmad ZA, Yeap SK, Ali AM, et al. scFv antibody: principles and clinical application. Clin Dev Immunol 2012;2012:980250.
29. Emadi S, Kasturirangan S, Wang MS, et al. Detecting morphologically distinct oligomeric forms of alpha-synuclein. J Biol Chem 2009;284:11048–11058.
30. Rockenstein E, Mallory M, Hashimoto M, et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002;68:568–578.
31. Dupont E, Prochiantz A, Joliot A. Penetratin story: an overview. Methods Mol Biol 2015;1324:29–37.
32. Skrlj N, Drevensek G, Hudoklin S, Romih R, Curin Serbec V, Dolinar M. Recombinant single-chain antibody with the Trojan peptide penetratin positioned in the linker region enables cargo transfer across the blood-brain barrier. Appl Biochem Biotechnol 2013;169:159–169.
33. Jones NH, Clabby ML, Dialynas DP, et al. Isolation of complementary DNA clones encoding the human lymphocyte glycoprotein T1/Leu-1. Nature 1986;323:346–349.
34. Zhou C, Emadi S, Sierks MR, Messer A. A human single-chain Fv intrabody blocks aberrant cellular effects of overexpressed alpha-synuclein. Mol Ther 2004;10:1023–1031.
35. Spencer B, Michael S, Shen J, et al. Lentivirus mediated delivery of neurosin promotes clearance of wild-type alpha-synuclein and reduces the pathology in an α-synuclein model of LBD. Mol Ther 2013;21:31–41.
36. Spencer B, Potkar R, Trejo M, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 2009;29:13578–13588.
37. Spencer B, Emadi S, Desplats P, et al. ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 2014;22:1753–1767.
38. Tiscornia G, Singer O, Verma IM. Production and purification of lentiviral vectors. Nat Protoc 2006;1:241–245.
39. Williams S, Schulz P, Sierks MR. A sensitive phage-based capture ELISA for sub-femtomolar detection of protein variants directly from biological samples. Biotechnol Prog 2015;31:289–298.
40. Williams SM, Schulz P, Sierks MR. Oligomeric α-sy nuclein and β-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases. Eur J Neurosci 2016;43:3–16.
41. Games D, Seubert P, Rockenstein E, et al. Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein. Am J Pathol 2013;182:940–953.
42. Fleming SM, Salcedo J, Hutson CB, et al. Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein. Neuroscience 2006;142:1245–1253.
43. Magen I, Fleming SM, Zhu C, et al. Cognitive deficits in a mouse model of pre-manifest Parkinson's disease. Eur J Neuorsci 2012;35:870–882.
44. Marr RA, Rockenstein E, Mukherjee A, et al. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 2003;23:1992–1996.
45. Franklin KBJ, Paxinos G. The mouse brain in stereotaxic coordinates. San Diego: Academic Press, 1997.
46. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000;287:1265–1269.
47. Overk CR, Cartier A, Shaked G, et al. Hippocampal neuronal cells that accumulate alpha-synuclein fragments are more vulnerable to Abeta oligomer toxicity via mGluR5–implications for dementia with Lewy bodies. Mol Neurodegener 2014;9:18.
48. Ubhi K, Rockenstein E, Mante M, et al. Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci 2010;30:6236–6246.
49. Xin W, Emadi S, Williams S, et al. Toxic oligomeric alpha-synuclein variants present in human parkinson's disease brains are differentially generated in mammalian cell models. Biomolecules 2015;5:1634–1651.
50. Maizel A, Bensaude O, Prochiantz A, Joliot A. A short region of its homeodomain is necessary for engrailed nuclear export and secretion. Development 1999;126:3183–3190.
51. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 1994;269:10444–10450.
52. Drin G, Cottin S, Blanc E, et al. Studies on the internalization mechanism of cationic cell-penetrating peptides. J Biol Chem 2003;278:31192–31201.
53. Spencer BJ, Verma IM. Targeted delivery of proteins across the blood-brain barrier. Proc Natl Acad Sci USA 2007;104:7594–7599.
54. Magen I, Chesselet MF. Genetic mouse models of Parkinson's disease the state of the art. Prog Brain Res 2010;184:53–87.
55. Price DL, Rockenstein E, Ubhi K, et al. Alterations in mGluR5 expression and signaling in Lewy body disease and in transgenic models of alpha-synucleinopathy–implications for excitotoxicity. PLoS One 2010;5:e14020.
56. Bouet V, Boulouard M, Toutain J, et al. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat Protoc 2009;4:1560–1564.
57. Bender A, Desplats P, Spencer B, et al. TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease. PLoS One 2013;8:e62277.
58. Marongiu R, Spencer B, Crews L, et al. Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem 2009;108:1561–1574.
59. Rockenstein E, Nuber S, Overk CR, et al. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain 2014;137(Pt 5):1496–1513.
60. Tsigelny IF, Crews L, Desplats P, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One 2008;3:e3135.
61. Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA 2011;108:4194–4199.
62. 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 USA 2009;106:13010–13015.
63. 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.
64. Mougenot AL, Nicot S, Bencsik A, et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 2012;33:2225–2228.
65. Ulusoy A, Rusconi R, Perez-Revuelta BI, et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med 2013;5:1051–1059.
66. Rey NL, Petit GH, Bousset L, et al. Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 2013;126:555–573.
67. Srimanee A, Regberg J, Langel U. Application of CPPs for brain delivery. Methods Mol Biol 2015;1324:349–356.
68. Stalmans S, Bracke N, Wynendaele E, et al. Cell-penetrating peptides selectively cross the blood-brain barrier in vivo. PLoS One 2015;10:e0139652.
69. Khafagy el S, Iwamae R, Kamei N, Takeda-Morishita M. Region-dependent role of cell-penetrating peptides in insulin absorption across the rat small intestinal membrane. AAPS J 2015;17:1427–1437.
70. Schildknecht S, Gerding HR, Karreman C, et al. Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. J Neurochem 2013;125:491–511.
71. Schmid AW, Fauvet B, Moniatte M, Lashuel HA. Alpha-synuclein post-translational modifications as potential biomarkers for Parkinson disease and other synucleinopathies. Mol Cell Proteomics 2013;12:3543–3558.
72. Vaikath NN, Majbour NK, Paleologou KE, et al. Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology. Neurobiol Dis 2015;79:81–99.