Abstract
Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed.
Similar content being viewed by others
References
Shults CW (2006) Lewy bodies. Proc Natl Acad Sci USA 103:1661–1668
Jellinger KA (2008) A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 116:1–16
Jellinger KA (2009) A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792:730–740
Ferman TJ, Boeve BF (2007) Dementia with Lewy bodies. Neurol Clin 25:741–760
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
Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108
Zarranz JJ, Alegre J, Gómez-Esteban JC et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173
Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2–S12
Braak H, Braak E (1997) Diagnostic criteria for neuropathological assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88
McKeith I, Mintzer J, Aarsland D et al (2004) Dementia with Lewy bodies. Lancet Neurol 3:19–28
McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-Snuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci U S A 95:6469–6473
Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 27:1405–1410
Der-Sarkissian A, Jao CC, Chen J, Langen R (2003) Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling. J Biol Chem 278:37530–37535
George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372
Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254
Ulmer TS, Bax A, Cole NB, Nussbaum RL (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280:9595–9603
Ulmer TS, Bax A (2005) Comparison of structure and dynamics of micelle-bound human alpha-synuclein and Parkinson disease variants. J Biol Chem 280:43179–43187
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
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
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 276:2380–1386
Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103:17–37
Levitan K, Chereau D, Cohen SI, Knowles TP, Dobson CM, Fink AL, Anderson JP, Goldstein JM, Millhauser GL (2011) Conserved C-terminal charge exerts a profound influence on the aggregation rate of α-synuclein. J Mol Biol 411:329–333
Bartels T, Choi JG, Selkoe DJ (2011) α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–110
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
Kahle PJ, Neumann M, Ozmen L, Haass C (2000) Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson’s disease-associated protein. Ann N Y Acad Sci 920:33–41
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
Takahashi M, Kanuka H, Fujiwara H, Koyama A, Hasegawa M, Miura M, Iwatsubo T (2003) Phosphorylation of alpha-synuclein characteristic of synucleinopathy lesions is recapitulated in alpha-synuclein transgenic Drosophila. Neurosci Lett 336:155–158
Anderson JP, Walker DE, Goldstein JM et al (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
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
Ellis CE, Schwartzberg PL, Grider TL, Fink DW, Nussbaum RL (2001) Alpha-synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases. J Biol Chem 276:3879–3884
Nakamura T, Yamashita H, Takahashi T, Nakamura S (2001) Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun 280:1085–1092
Chen L, Periquet M, Wang X, Negro A, McLean PJ, Hyman BT, Feany MB (2009) Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest 119:3257–3265
Pronin AN, Morris AJ, Surguchov A, Benovic JL (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem 275:26515–26522
Arawaka S, Wada M, Goto S et al (2006) The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson’s disease. J Neurosci 26:9227–9238
Inglis KJ, Chereau D, Brigham EF et al (2009) Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem 284:2598–25602
Mbefo MK, Paleologou KE, Boucharaba A, Oueslati A, Schell H, Fournier M, Olschewski D, Yin G, Zweckstetter M, Masliah E, Kahle PJ, Hirling H, Lashuel HA (2010) Phosphorylation of synucleins by members of the Polo-like kinase family. J Biol Chem 285:2807–2822
Waxman EA, Giasson BI (2011) Characterization of kinases involved in the phosphorylation of aggregated α-synuclein. J Neurosci Res 89:231–247
Paleologou KE, Oueslati A, Shakked G et al (2010) Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 30:3184–3198
Ryu MY, Kim DW, Arima K, Mouradian MM, Kim SU, Lee G (2008) Localization of CKII beta subunits in Lewy bodies of Parkinson’s disease. J Neurol Sci 266:9–12
Zhou J, Broe M, Huang Y, Anderson JP, Gai WP, Milward EA, Porritt M, Howells D, Hughes AJ, Wang X, Halliday GM (2011) Changes in the solubility and phosphorylation of α-synuclein over the course of Parkinson’s disease. Acta Neuropathol 121:695–704
Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654
Schulz-Schaeffer WJ (2010) The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 120:131–143
Tanji K, Mori F, Mimura J, Itoh K, Kakita A, Takahashi H, Wakabayashi K (2010) Proteinase K-resistant alpha-synuclein is deposited in presynapses in human Lewy body disease and A53T alpha-synuclein transgenic mice. Acta Neuropathol 120:145–154
Visanji NP, Wislet-Gendebien S, Oschipok LW, Zhang G, Aubert I, Fraser PE, Tandon A (2011) Effect of Ser-129 phosphorylation on interaction of {alpha}-synuclein with synaptic and cellular membranes. J Biol Chem 286:35863–35873
Kim EJ, Sung JY, Lee HJ, Rhim H, Hasegawa M, Iwatsubo T, Min do S, Kim J, Paik SR, Chung KC (2006) Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 281:33250–33257
Sadowski M, Sarcevic B (2010) Mechanisms of mono- and poly-ubiquitination: ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine. Cell Div 5:19
Petroski MD, Deshaies RJ (2003) Context of multiubiquitin chain attachment influences the rate of Sic1 degradation. Mol Cell 11:1435–1444
Petroski M, Deshaies R (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6:8–20
Nemani M, Linares-Cruz G, Bruzzoni-Giovanelli H et al (1996) Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. Proc Natl Acad Sci USA 93:9039–9042
Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated a-synuclein is ubiquitinated in a-synucleinopathy lesions. J Biol Chem 277:49071–49076
Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of a-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278:44405–44411
Nonaka T, Iwatsubo T, Hasegawa M (2005) Ubiquitination of alpha-synuclein. Biochemistry 44:361–368
Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269
Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150
Wheeler TC, Chin LS, Li Y, Roudabush FL, Li L (2002) Regulation of synaptophysin degradation by mammalian homologues of seven in absentia. J Biol Chem 277:10273–10282
Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S (2004) Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson’s disease. Proc Natl Acad Sci USA 101:5500–5505
Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S (2007) Monoubiquitination of a-synuclein by SIAH promotes its aggregation in dopaminergic cells. J Biol Chem 283:3316–3328
Lee JT, Wheeler TC, Li L, Chin LS (2008) Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 17:906–917
House CM, Hancock NC, Möller A, Cromer BA, Fedorov V, Bowtell DD, Parker MW, Polekhina G (2006) Elucidation of the substrate binding site of Siah ubiquitin ligase. Structure 14:695–701
Demand J, Alberti S, Patterson C, Hohfeld J (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11:1569–1577
Murata S, Minami Y, Minami M, Chiba T, Tanaka K (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2:1133–1138
Kalia LV, Kalia SK, Chau H, Lozano AM, Hyman BT, McLean PJ (2011) Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 6:e14695
Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ (2005) The cochaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727–23734
Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, McLean PJ (2008) CHIP targets toxic alpha-synuclein oligomers for degradation. J Biol Chem 283:17962–17968
Kalia SK, Lee S, Smith PD, Liu L, Crocker SJ, Thorarinsdottir TE, Glover JR, Fon EA, Park DS, Lozano AM (2004) BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron 44:931–945
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055
Zhu J, Chu CT (2010) Mitochondrial dysfunction in Parkinson’s disease. J Alzheimers Dis 20(Suppl 2):S325–S334
Cookson MR, Bandmann O (2010) Parkinson’s disease: insights from pathways. Hum Mol Genet 19:R21–R27
Jendrach M, Gispert S, Ricciardi F, Klinkenberg M, Schemm R, Auburger G (2009) The mitochondrial kinase PINK1, stress response and Parkinson’s disease. J Bioenerg Biomembr 41:481–486
Leong SL, Pham CL, Galatis D, Fodero-Tavoletti MT, Perez K, Hill AF, Masters CL, Ali FE, Barnham KJ, Cappai R (2009) Formation of dopamine-mediated alpha-synuclein-soluble oligomers requires methionine oxidation. Free Radic Biol Med 46:1328–1337
Zhou W, Long C, Reaney SH, Di Monte DA, Fink AL, Uversky VN (2010) Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions. Biochim Biophys Acta 1802:322–330
Herrera FE, Chesi A, Paleologou KE, Schmid A, Munoz A, Vendruscolo M, Gustincich S, Lashuel HA, Carloni P (2008) Inhibition of alpha-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. PLoS One 3:e3394
Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989
Liu Y, Qiang M, Wei Y, He R (2011) A novel molecular mechanism for nitrated alpha-synuclein-induced cell death. J Mol Cell Biol 3:239–249
Danielson SR, Held JM, Schilling B, Oo M, Gibson BW, Andersen JK (2009) Preferentially increased nitration of alpha-synuclein at tyrosine-39 in a cellular oxidative model of Parkinson’s disease. Anal Chem 81:7823–7828
Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376
Yu Z, Xu X, Xiang Z, Zhou J, Zhang Z, Hu C, He C (2010) Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats. PLoS One 5:e9956
Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698
Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) 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 99:8968–8973
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533
Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jäkälä P, Beyreuther K, Masters CL, Li QX (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76:87–96
Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884
Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jäkälä P, Hartmann T, Price DL, Lee MK (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci U S A 102:2162–2167
Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA (2000) Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci U S A 97:4897–4902
Murray IV, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, Trojanowski JQ, Lee VM (2003) Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42:8530–8540
Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280:22670–22678
Ulusoy A, Febbraro F, Jensen PH, Kirik D, Romero-Ramos M (2010) Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology. Eur J Neurosci 32:409–422
Bennett MC, Bishop JF, Leng Y, Chock PB, Chase TN, Mouradian MM (1999) Degradation of alphasynuclein by proteasome. J Biol Chem 274:33855–33858
Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alphasynuclein by chaperone-mediated autophagy. Science 305:1292–1295
Tofaris GK, Layfield R, Spillantini MG (2001) alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509:22–26
Liu CW, Corboy MJ, DeMartino GN, Thomas PJ (2003) Endoproteolytic activity of the proteasome. Science 299:408–411
Lewis KA, Yaeger A, DeMartino GN, Thomas PJ (2010) Accelerated formation of alpha-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations. J Bioenerg Biomembr 42:85–95
Takahashi M, Ko LW, Kulathingal J, Jiang P, Sevlever D, Yen SH (2007) Oxidative stress-induced phosphorylation, degradation and aggregation of alpha-synuclein are linked to upregulated CK2 and cathepsin D. Eur J Neurosci 26:863–874
Sevlever D, Jiang P, Yen SH (2008) Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47:9678–9687
Billger M, Wallin M, Karlsson JO (1988) Proteolysis of tubulin and microtubule-associated proteins 1 and 2 by calpain I and II. Difference in sensitivity of assembled and disassembled microtubules. Cell Calcium 9:33–44
Bednarski E, Vanderklish P, Gall C, Saido TC, Bahr BA, Lynch G (1995) Translational suppression of calpain I reduces NMDA-induced spectrin proteolysis and pathophysiology in cultured hippocampal slices. Brain Res 694:147–157
Mercken M, Grynspan F, Nixon RA (1995) Differential sensitivity to proteolysis by brain calpain of adult human tau, fetal human tau and PHF-tau. FEBS Lett 368:10–14
Mishizen-Eberz AJ, Guttmann RP, Giasson BI, Day GA 3rd, Hodara R, Ischiropoulos H, Lee VM, Trojanowski JQ, Lynch DR (2003) Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J Neurochem 86:836–847
Mishizen-Eberz AJ, Norris EH, Giasson BI, Hodara R, Ischiropoulos H, Lee VM, Trojanowski JQ, Lynch DR (2005) Cleavage of alpha-synuclein by calpain: potential role in degradation of fibrillized and nitrated species of alpha-synuclein. Biochemistry 44:7818–7829
Dufty BM, Warner LR, Hou ST, Jiang SX, Gomez-Isla T, Leenhouts KM, Oxford JT, Feany MB, Masliah E, Rohn TT (2007) Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation. Am J Pathol 170:1725–1738
Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N (2003) Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet 12:2625–2635
Kasai T, Tokuda T, Yamaguchi N, Watanabe Y, Kametani F, Nakagawa M, Mizuno T (2008) Cleavage of normal and pathological forms of alpha-synuclein by neurosin in vitro. Neurosci Lett 436:52–56
Kim YS, Choi DH, Block ML, Lorenzl S, Yang L, Kim YJ, Sugama S, Cho BP, Hwang O, Browne SE, Kim SY, Hong JS, Beal MF, Joh TH (2007) A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J 21:179–187
Choi DH, Kim EM, Son HJ, Joh TH, Kim YS, Kim D, Flint Beal M, Hwang O (2008) A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem 106:405–415
Choi DH, Hwang O, Lee KH, Lee J, Beal MF, Kim YS (2011) DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death. Antioxid Redox Signal 14:2137–2150
Choi DH, Kim YJ, Kim YG, Joh TH, Beal MF, Kim YS (2011) Role of matrix metalloproteinase 3-mediated alpha-synuclein cleavage in dopaminergic cell death. J Biol Chem 286:14168–14177
Uversky VN, Fink AL (2002) Amino acid determinants of alpha-synuclein aggregation: putting together pieces of the puzzle. FEBS Lett 522:9–13
Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem 277:11970–11978
Cho MK, Nodet G, Kim HY, Jensen MR, Bernado P, Fernandez CO, Becker S, Blackledge M, Zweckstetter M (2009) Structural characterization of alpha-synuclein in an aggregation prone state. Protein Sci 18:1840–1846
Bisaglia M, Trolio A, Bellanda M, Bergantino E, Bubacco L, Mammi S (2006) Structure and topology of the non-amyloid-beta component fragment of human alpha-synuclein bound to micelles: implications for the aggregation process. Protein Sci 15:1408–1416
Bodner CR, Maltsev AS, Dobson CM, Bax A (2010) Differential phospholipid binding of alpha-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biochemistry 49:862–871
Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800–7807
Perrin RJ, Woods WS, Clayton DF, George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958–41962
Li J, Uversky VN, Fink AL (2001) Effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40:11604–11613
Ono K, Ikeda T, Takasaki J, Yamada M (2011) Familial Parkinson disease mutations influence α-synuclein assembly. Neurobiol Dis 43:715–724
Wang W, Perovic I, Chittuluru J et al (2011) A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 108:17797–17802
McClendon S, Rospigliosi CC, Eliezer D (2009) Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH. Protein Sci 18:1531–1540
Yin J, Han J, Zhang C, Ma QL, Li X, Cheng F, Liu G, Li Y, Uéda K, Chan P, Yu S (2011) C-terminal part of α-synuclein mediates its activity in promoting proliferation of dopaminergic cells. J Neural Transm 118:1155–1164
Jao CC, Der-Sarkissian A, Chen J, Langen R (2004) Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling. Proc Natl Acad Sci U S A 101:8331–8336
Heise H, Hoyer W, Becker S, Andronesi OC, Riedel D, Baldus M (2005) Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci U S A 102:15871–15876
Beyer K, Lao JI, Carrato C, Mate JL, López D, Ferrer I, Ariza A (2004) Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol 30:601–607
Beyer K, Domingo-Sàbat M, Humbert J, Carrato C, Ferrer I, Ariza A (2008) Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease. Neurogenetics 9:163–172
Kalivendi SV, Yedlapudi D, Hillard CJ, Kalyanaraman B (2010) Oxidants induce alternative splicing of alpha-synuclein: implications for Parkinson’s disease. Free Radic Biol Med 48:377–383
Klegeris A, McGeer PL (2007) Complement activation by islet amyloid polypeptide (IAPP) and alpha-synuclein 112. Biochem Biophys Res Commun 357:1096–1099
Loeffler DA, Camp DM, Conant SB (2006) Complement activation in the Parkinson’s disease substantia nigra: an immunocytochemical study. J Neuroinflammation 3:29
McGeer PL, McGeer EG (2004) Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 10(Suppl 1):S3–S7
McCarthy JJ, Linnertz C, Saucier L, Burke JR, Hulette CM, Welsh-Bohmer KA, Chiba-Falek O (2011) The effect of SNCA 3′ region on the levels of SNCA-112 splicing variant. Neurogenetics 12:59–64
Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T, Berg D, Wüllner U, Meitinger T, Gasser T (2005) Multiple regions of alpha-synuclein are associated with Parkinson’s disease. Ann Neurol 57:535–541
Pals P, Lincoln S, Manning J, Heckman M, Skipper L, Hulihan M, Van den Broeck M, De Pooter T, Cras P, Crook J, Van Broeckhoven C, Farrer MJ (2004) Alpha-synuclein promoter confers susceptibility to Parkinson’s disease. Ann Neurol 56:591–595
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211
Beyer K, Humbert J, Ferrer A, Lao JI, Latorre P, Lopez D, Tolosa E, Ferrer I, Ariza A (2007) A variable poly-T sequence modulates alpha-synuclein isoform expression and is associated with aging. J Neurosci Res 85:1538–1546
Beyer K, Domingo-Sábat M, Lao JI, Carrato C, Ferrer I, Ariza A (2008) Identification and characterization of a new alpha-synuclein isoform and its role in Lewy body diseases. Neurogenetics 9:15–23
Ma KL, Yuan YH, Song LK, Han N, Chen NH (2011) Over-expression of α-synuclein 98 triggers intracellular oxidative stress and enhances susceptibility to rotenone. Neurosci Lett 491:148–152
Beyer K, Domingo-Sàbat M, Santos C, Tolosa E, Ferrer I, Ariza A (2010) The decrease of β-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies. Brain 133:3724–3733
Acknowledgments
We thank Lukas Lao Beyer for his assistance on drawing Fig. 8. This work was supported by Spain’s Ministry of Health FIS grant CP09/00102.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Beyer, K., Ariza, A. Alpha-Synuclein Posttranslational Modification and Alternative Splicing as a Trigger for Neurodegeneration. Mol Neurobiol 47, 509–524 (2013). https://doi.org/10.1007/s12035-012-8330-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-012-8330-5