Mimicking phosphorylation at serine 87 inhibits the aggregation of human α-synuclein and protects against its toxicity in a rat model of parkinson's disease

Journal of Neuroscience

Volumn 32, Issue 5, 2012, Pages 1536-1544

  Oueslati, Abid ^a   Paleologou, Katerina E ^a   Schneider, Bernard L ^b   Aebischer, Patrick ^b   Lashuel, Hilal A ^a  

^a Laboratory of Molecular and Chemical Biology of Neurodegeneration   (Switzerland)

^b EPFL   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; PARVOVIRUS VECTOR; PROTEINASE K; SERINE;

ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHEMICAL ANALYSIS; CONTROLLED STUDY; CORRELATIONAL STUDY; DOPAMINERGIC NERVE CELL; IMMUNOHISTOCHEMISTRY; MALE; MOTOR DYSFUNCTION; NEUROPATHOLOGY; NEUROTOXICITY; NIGRONEOSTRIATAL SYSTEM; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; RAT; SUBSTANTIA NIGRA;

ALPHA-SYNUCLEIN; ANIMALS; CORPUS STRIATUM; DISEASE MODELS, ANIMAL; GENE TRANSFER TECHNIQUES; HUMANS; MALE; MUTATION; PARKINSON DISEASE; PHOSPHORYLATION; RATS; RATS, WISTAR; SERINE;

EID: 84856667162     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.3784-11.2012     Document Type: Article

References (46)

1. Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739-29752.
2. Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, Sage D, Abbas-Terki T, Iwatsubo T, Unser M, Aebischer P (2009) Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease. Hum Mol Genet 18:872-887.
3. Baens M, Noels H, Broeckx V, Hagens S, Fevery S, Billiau AD, Vankelecom H, Marynen P (2006) The dark side of EGFP: defective polyubiquitination. PLoS One 1:e5420.
4. Braak H, Braak E (2000) Pathoanatomy of Parkinson's disease. J Neurol 247 [Suppl 2]:3-10.
5. Chau KY, Ching HL, Schapira AH, Cooper JM (2009) Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson's disease pathogenesis. J Neurochem 110:1005-1013.
6. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657-663.
7. Copeland M. XA, Turi T., Mouradian M. M., Braithwaite S. P., Martone R. L (2011) Parkinson's disease biomarker development: immunoprecipitation LC-MS/MS to quantitatively detect phosphorylated alpha-synuclein in human CSF. Paper presented at the 10th International Conference on Alzheimer's and Parkinson's Diseases, Barcelona, Spain, March.
8. Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB, Gollomp SM, Grossman M, Lee VM, Trojanowski JQ (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59:830-841.
9. El-Agnaf OM, Jakes R, Curran MD, Middleton D, Ingenito R, Bianchi E, Pessi A, Neill D, Wallace A (1998) Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Lett 440:71-75.
10. Fournier M, Vitte J, Garrigue J, Langui D, Dullin JP, Saurini F, Hanoun N, Perez-Diaz F, Cornilleau F, Joubert C, Ardila-Osorio H, Traver S, Duchateau R, Goujet-Zalc C, Paleologou K, Lashuel HA, Haass C, Duyckaerts C, Cohen-Salmon C, Kahle PJ, et al. (2009) Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. PLoS One 4:e6629.
11. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160-164.
12. Giasson BI, Murray IV, Trojanowski JQ, Lee VM (2001) A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem 276:2380-2386.
13. Gorbatyuk OS, Li S, Sullivan LF, Chen W, Kondrikova G, Manfredsson FP, Mandel RJ, Muzyczka N (2008) The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci U S A 105:763-768.
14. Han H, Weinreb PH, Lansbury PT Jr (1995) The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease? Chem Biol 2:163-169.
15. Irizarry MC, Growdon W, Gomez-Isla T, Newell K, George JM, Clayton DF, Hyman BT (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J Neuropathol Exp Neurol 57: 334-337.
16. Iwai A, Yoshimoto M, Masliah E, Saitoh T (1995) Non-A beta component of Alzheimer's disease amyloid (NAC) is amyloidogenic. Biochemistry 34:10139-10145.
17. Jakes R, Crowther RA, Lee VM, Trojanowski JQ, Iwatsubo T, Goedert M (1999) Epitope mapping of LB509, a monoclonal antibody directed against human alpha-synuclein. Neurosci Lett 269:13-16.
18. Jan A, Gokce O, Luthi-Carter R, Lashuel HA (2008) The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. J Biol Chem 283:28176-28189.
19. Jan A, Hartley DM, Lashuel HA (2010) Preparation and characterization of toxic Abeta aggregates for structural and functional studies in Alzheimer's disease research. Nat Protoc 5:1186-1209.
20. Kahle PJ, Neumann M, Ozmen L, Müller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215-2225.
21. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583-588.
22. Khandelwal PJ, Dumanis SB, Feng LR, Maguire-Zeiss K, Rebeck G, Lashuel HA, Moussa CE (2010) Parkinson-related parkin reduces alpha-Synuclein phosphorylation in a gene transfer model. Mol Neurodegener 5:47.
23. Kim EJ, Sung JY, Lee HJ, Rhim H, Hasegawa M, Iwatsubo T, Mindo S, Kim J, Paik SR, Chung KC (2006) Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 281:33250-33257.
24. Kirik D, Georgievska B, Burger C, Winkler C, Muzyczka N, Mandel RJ, Bjorklund A (2002a) Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. Proc Natl Acad Sci U S A 99:4708-4713.
25. Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A (2002b) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780-2791.
26. Koprich JB, Johnston TH, Reyes MG, Sun X, Brotchie JM (2010) Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease. Mol Neurodegener 5:43.
27. Kragh CL, Lund LB, Febbraro F, Hansen HD, Gai WP, El-Agnaf O, Richter-Landsberg C, Jensen PH (2009) {alpha}-Synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. J Biol Chem 284:10211-10222.
28. Léger J, Kempf M, Lee G, Brandt R (1997) Conversion of serine to aspartate imitates phosphorylation-induced changes in the structure and function of microtubule-associated protein tau. J Biol Chem 272:8441-8446.
29. Lou H, Montoya SE, Alerte TN, Wang J, Wu J, Peng X, Hong CS, Friedrich EE, Mader SA, Pedersen CJ, Marcus BS, McCormack AL, Di Monte DA, Daubner SC, Perez RG (2010) Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. J Biol Chem 285:17648-17661.
30. Luk KC, Song C, O'Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VM (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A 106:20051-20056.
31. Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M, Koyama S, Kato T (2010) Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J BiolChem 285:40732-40744.
32. McFarland MA, Ellis CE, Markey SP, Nussbaum RL (2008) Proteomics analysis identifies phosphorylation-dependent alpha-synuclein protein interactions. Mol Cell Proteomics 7:2123-2137.
33. McFarland NR, Fan Z, Xu K, Schwarzschild MA, Feany MB, Hyman BT, McLean PJ (2009) Alpha-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of Parkinson disease. J Neuropathol Exp Neurol 68:515-524.
34. Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 110:1429-1439.
35. Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C (2000) Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J Biol Chem 275:390-397.
36. Oueslati A, Fournier M, Lashuel HA (2010) Role of post-translational modifications in modulating the structure, function and toxicity of alphasynuclein: implications for Parkinson's disease pathogenesis and therapies. Prog Brain Res 183:115-145.
37. Paleologou KE, Schmid AW, Rospigliosi CC, Kim HY, Lamberto GR, Fredenburg RA, Lansbury PT Jr, Fernandez CO, Eliezer D, Zweckstetter M, Lashuel HA (2008) Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein. J Biol Chem 283:16895-16905.
38. Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim HY, Lamberto GR, Fernandez CO, Schmid A, Chegini F, Gai WP, Chiappe D, Moniatte M, Schneider BL, Aebischer P, Eliezer D, Zweckstetter M, Masliah E, Lashuel HA (2010) Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 30:3184-3198.
39. Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777-787.
40. Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL, Dawson TM, Iwatsubo T, Ross CA (2005) Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25:5544-5552.
41. Sugeno N, Takeda A, Hasegawa T, Kobayashi M, Kikuchi A, Mori F, Wakabayashi K, Itoyama Y (2008) Serine 129 phosphorylation of alphasynuclein induces unfolded protein response-mediated cell death. J Biol Chem 283:23179-23188.
42. Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 90:11282-11286.
43. Waxman EA, Giasson BI (2008) Specificity and regulation of casein kinasemediated phosphorylation of alpha-synuclein. J Neuropathol Exp Neurol 67:402-416.
44. West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51-61.
45. Wu B, Liu Q, Duan C, Li Y, Yu S, Chan P, Uéda K, Yang H (2011) Phosphorylation of alpha-synuclein upregulates tyrosine hydroxylase activity in MN9D cells. Acta Histochem 113:32-35.
46. Zhou W, Milder JB, Freed CR (2008) Transgenic mice overexpressing tyrosine-to-cysteine mutant human alpha-synuclein: a progressive neurodegenerative model of diffuse Lewy body disease. J Biol Chem 283: 9863-9870.