Alpha-synuclein

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Synuclein, alpha (non A4 component of amyloid precursor)
PBB Protein SNCA image.jpg
PDB rendering based on 1xq8[1].
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SNCA ; NACP; PARK1; PARK4; PD1
External IDs OMIM163890 MGI1277151 HomoloGene293 ChEMBL: 6152 GeneCards: SNCA Gene
RNA expression pattern
PBB GE SNCA 204466 s at tn.png
PBB GE SNCA 204467 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6622 20617
Ensembl ENSG00000145335 ENSMUSG00000025889
UniProt P37840 O55042
RefSeq (mRNA) NM_000345 NM_001042451
RefSeq (protein) NP_000336 NP_001035916
Location (UCSC) Chr 4:
90.65 – 90.76 Mb
Chr 6:
60.73 – 60.83 Mb
PubMed search [1] [2]

Alpha-synuclein is a protein that is abundant in the human brain.[2] Smaller amounts are found in the heart, muscles, and other tissues.[2] In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals.[2] Within these structures, alpha-synuclein interacts with phospholipids [3] and proteins.[2] Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.[2]

Although the function of alpha-synuclein is not well understood, studies suggest that it plays an important role in maintaining a supply of synaptic vesicles in presynaptic terminals.[2] It may also help regulate the release of dopamine, a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.[2]

The human Alpha-synuclein protein is made of 140 amino acids, and is encoded by the SNCA gene.[4][5][6] An alpha-synuclein fragment, known as the non-Abeta component (NAC) of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, was shown to be a fragment of its precursor protein, NACP.[4] It was later determined that NACP was the human homologue of Torpedo synuclein. Therefore, NACP is now referred to as human alpha-synuclein.

Tissue expression[edit]

Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, making up as much as 1% of all proteins in the cytosol of brain cells.[7] It is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. It is predominantly a neuronal protein, but can also be found in the neuroglial cells.[citation needed] In melanocytic cells, SNCA protein expression may be regulated by MITF.[8]

It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus.[9] Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms,[10] with roughly 15% of synuclein being membrane-bound in any moment in neurons.[11]

Recently, it has been shown that alpha-synuclein is localized in neuronal mitochondria.[12][13] Alpha-synuclein is highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum,and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on complex I activity of mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.[13]

At least three isoforms of synuclein are produced through alternative splicing.[14] The majority form of the protein, and the one most investigated, is the full 140 aminoacids-long transcript. Other isoforms are alpha-synuclein-126, where exon 3 is lost and lacks residues 41-54; and alpha-synuclein-112,[15] which lacks residue 103-130 due to loss of exon 5.[14]

Structure[edit]

Alpha-synuclein in solution is considered to be an intrinsically disordered protein, i.e. it lacks a single stable 3D structure.[16] As of 2014, an increasing number of reports suggest, however, the presence of partial structures or mostly structured oligomeric states in the solution structure of alpha-synuclein even in the absence of lipids. This trend is also supported by a large number of single molecule (optical tweezers) measurements on single copies of monomeric alpha-synuclein as well as covalently enforced dimers or tetramers of alpha-synuclein.[17]

Functions[edit]

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.[18] It has been shown that alpha-synuclein significantly interacts with tubulin,[19] and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau.[20]

Recent evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes.[21][22] In particular, it simultaneously binds to phospholipids of the plasma membrane via its N-terminus domain and to synaptobrevin-2 via its C-terminus domain, with increased importance during synaptic activity.[23] Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.[24]

Apparently, alpha-synuclein is essential for normal development of the cognitive functions. Knock-out mice with the targeted inactivation of the expression of alpha-synuclein show impaired spatial learning and working memory.[25]

Interaction with lipid membranes[edit]

Experimental evidence has been collected on the interaction of alpha-synuclein with membrane and its involvement with membrane composition and turnover. Yeast genome screening has found that several genes that deal with lipid metabolism play a role in alpha-synuclein toxicity.[26] Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.[27]

Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids.[27] Alpha-synuclein forms an extended helical structure on small unilamellar vesicles.[28] A preferential binding to small vesicles has been found.[29] The binding of alpha-synuclein to lipid membranes has complex effects on the latter, altering the bilayer structure and leading to the formation of small vesicles.[30] Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.[31] Using cryo-EM it was shown that these are micellar tubes of ~5-6 nm diameter.[32] Alpha-synuclein has also been shown to form lipid disc-like particles similar to apolipoproteins [3].[33] Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane.[34]

Photomicrographs of regions of substantia nigra in a patient showing Lewy bodies and Lewy neurites in various magnifications

Sequence[edit]

Alpha-synuclein primary structure is usually divided in three distinct domains:

  • Residues 1-60: An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequence KTKEGV. This sequence has a structural alpha helix propensity similar to apolipoproteins-binding domains[35]
  • Residues 61-95: A central hydrophobic region which includes the non-amyloid-β component (NAC) region, involved in protein aggregation[4]
  • Residues 96-140: a highly acidic and proline-rich region which has no distinct structural propensity

Autoproteolytic Activity[edit]

The use of high-resolution ion-mobility mass spectrometry (IMS-MS) on HPLC-purified alpha-synuclein in vitro has shown alpha-synuclein to be autoproteolytic (self-proteolytic), generating a variety of small molecular weight fragments upon incubation.[36] The 14.46 kDa protein was found to generate numerous smaller fragments, including 12.16 kDa (amino acids 14-133) and 10.44 kDa (40-140) fragments formed through C- and N-terminal truncation and a 7.27 kDa C-terminal fragment (72-140). The 7.27 kDa fragment, which contains the majority of the NAC region, aggregated considerably faster than full-length alpha-synuclein. It is possible that these autoproteolytic products play a role as intermediates or cofactors in the aggregation of alpha-synuclein in vivo.

Clinical significance[edit]

Positive α-Synuclein staining of a Lewy body in a patient with Parkinson's disease.

Classically considered an unstructured soluble protein, new evidence suggests that unmutated α-synuclein forms a stably folded tetramer that resists aggregation.[37] Nevertheless, alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.[38][39] These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein;[40] however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.[41] Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.[42]

The aggregation mechanism of alpha-synuclein is uncertain. There is evidence of a structured intermediate rich in beta structure that can be the precursor of aggregation and, ultimately, Lewy bodies.[43] A single molecule study in 2008 suggests alpha-synuclein exists as a mix of unstructured, alpha-helix, and beta-sheet-rich conformers in equilibrium. Mutations or buffer conditions known to improve aggregation strongly increase the population of the beta conformer, thus suggesting this could be a conformation related to pathogenic aggregation.[44] Among the strategies for treating synucleinopathies are compounds that inhibit aggregation of alpha-synuclein. It has been shown that the small molecule cuminaldehyde inhibits fibrillation of alpha-synuclein.[45] The Epstein-Barr virus has been implicated in these disorders.[46]

In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. Three point mutations have been identified thus far: A53T,[47] A30P,[48] and E46K.[49] Genomic duplication and triplication of the gene appear to be a rare cause of Parkinson's disease in other lineages, although more common than point mutations.[50] Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease.

Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies.[51]

Events in α-synuclein toxicity.[52] The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons.

Certain sections of the alpha-synuclein protein may play a role in the tauopathies.[53]

Protein-protein interactions[edit]

Alpha-synuclein has been shown to interact with

See also[edit]

  • Synuclein
  • Contursi Terme - the village in Italy where a mutation in the α-synuclein gene led to a family history of Parkinson's disease

References[edit]

  1. ^ Ulmer, T. S.; Bax, A.; Cole, N. B.; Nussbaum, R. L. (2004). "Structure and Dynamics of Micelle-bound Human  -Synuclein". Journal of Biological Chemistry 280 (10): 9595–9603. doi:10.1074/jbc.M411805200. PMID 15615727.  edit
  2. ^ a b c d e f g "Genetics Home Reference: SNCA". U.S. National Library of Medicine. 12 Nov 2013. Retrieved 14 Nov 2013. 
  3. ^ Chandra, S; X. Chen; J. Rizo; R. Jahn; T. C. Südhof (2003). "A broken α-helix in folded α-Synuclein". J. Biol. Chem 278 (15313): 15313–8. doi:10.1074/jbc.M213128200. PMID 12586824. 
  4. ^ a b c Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (December 1993). "Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America 90 (23): 11282–6. doi:10.1073/pnas.90.23.11282. PMC 47966. PMID 8248242. 
  5. ^ Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (October 2001). "Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms". J. Alzheimers Dis. 3 (5): 485–494. PMID 12214035. 
  6. ^ Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2002). "Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms: Erratum p489 Fig 3". J. Alzheimers Dis. 4 (4): 337. 
  7. ^ Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T (February 1995). "The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system". Neuron 14 (2): 467–75. doi:10.1016/0896-6273(95)90302-X. PMID 7857654. 
  8. ^ Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 
  9. ^ Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P (March 2007). "Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody". Neuroscience 145 (2): 539–55. doi:10.1016/j.neuroscience.2006.12.028. PMID 17275196. 
  10. ^ McLean PJ, Kawamata H, Ribich S, Hyman BT (March 2000). "Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations". J. Biol. Chem. 275 (12): 8812–6. doi:10.1074/jbc.275.12.8812. PMID 10722726. 
  11. ^ Lee HJ, Choi C, Lee SJ (January 2002). "Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form". J. Biol. Chem. 277 (1): 671–8. doi:10.1074/jbc.M107045200. PMID 11679584. 
  12. ^ Zhang L, Zhang C, Zhu Y, Cai Q, Chan P, Uéda K, Yu S, Yang H (December 2008). "Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody". Brain Res 1244: 40–52. doi:10.1016/j.brainres.2008.08.067. PMID 18817762. 
  13. ^ a b Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S (May 2009). "Alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity". Neurosci. Lett. 454 (3): 187–92. doi:10.1016/j.neulet.2009.02.056. PMID 19429081. 
  14. ^ a b Beyer K (September 2006). "Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers". Acta Neuropathol. 112 (3): 237–51. doi:10.1007/s00401-006-0104-6. PMID 16845533. 
  15. ^ Uéda K, Saitoh T, Mori H (December 1994). "Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer's disease amyloid.". Biochem. Biophys. Res. Commun. 205 (2): 1366–72. doi:10.1006/bbrc.1994.2816. PMID 7802671. 
  16. ^ van Rooijen BD, van Leijenhorst-Groener KA, Claessens MM, Subramaniam V (December 2009). "Tryptophan fluorescence reveals structural features of alpha-synuclein oligomers.". J Mol Biol. 394 (5): 826–33. doi:10.1016/j.jmb.2009.10.021. PMID 19837084. 
  17. ^ Neupane K, Solanki A, Sosova I, Belov M, Woodside MT (January 2014). "Diverse Metastable Structures Formed by Small Oligomers of α-Synuclein Probed by Force Spectroscopy". PLOS ONE 9 (1): e86495. doi:10.1371/journal.pone.0086495. PMC 3901707. PMID 24475132. 
  18. ^ George JM, Jin H, Woods WS, Clayton DF (August 1995). "Characterization of a novel protein regulated during the critical period for song learning in the zebra finch". Neuron 15 (2): 361–72. doi:10.1016/0896-6273(95)90040-3. PMID 7646890. 
  19. ^ Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Uéda K. (Jan 2002). "Tubulin seeds alpha-synuclein fibril formation.". J. Biol. Chem. 277 (3): 2112–7. doi:10.1074/jbc.M102981200. PMID 11698390. 
  20. ^ Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, Hisanaga S, Uéda K (August 2004). "Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein". J. Alzheimers Dis. 6 (4): 435–42; discussion 443–9. PMID 15345814. 
  21. ^ Bonini NM, Giasson BI (November 2005). "Snaring the function of alpha-synuclein". Cell 123 (3): 359–61. doi:10.1016/j.cell.2005.10.017. PMID 16269324. 
  22. ^ Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC (November 2005). "Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration". Cell 123 (3): 383–96. doi:10.1016/j.cell.2005.09.028. PMID 16269331. 
  23. ^ Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC (September 2010). "Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro". Science 329 (5999): 1663–7. doi:10.1126/science.1195227. PMC 3235365. PMID 20798282. 
  24. ^ A. A. Cooper, A. D. Gitler, A. Cashikar, C. M. Haynes, K. J. Hill, B. Bhullar,K. Liu, K. Xu, K. E. Strathearn, F. Liu, S. Cao, K. A. Caldwell, G. A.Caldwell, G. Marsischky, R. D. Kolodner, J. Labaer, J. C. Rochet, N. M.Bonini, and S. Lindquist. (2006). "Alpha-synuclein blocks ER-golgi traffic and Rab1 rescues neuron loss in Parkinson’s models". Science 313 (5785): 324–328. doi:10.1126/science.1129462. PMC 1983366. PMID 16794039. 
  25. ^ Kokhan VS, Afanasyeva MA, Van'kin GI. (May 2012). "α-Synuclein knockout mice have cognitive impairments.". Behav. Brain. Res. 231 (1): 226–230. doi:10.1016/j.bbr.2012.03.026. PMID 22469626. 
  26. ^ Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ (December 2003). "Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein". Science 302 (5651): 1769–72. doi:10.1126/science.1090389. PMID 14657499. 
  27. ^ a b Uversky VN (October 2007). "Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation". J. Neurochem. 103 (1): 17–37. doi:10.1111/j.1471-4159.2007.04764.x. PMID 17623039. 
  28. ^ Jao CC, Hegde BG, Chen J, Haworth IS, Langen R (December 2008). "Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement". Proceedings of the National Academy of Sciences of the United States of America 105 (50): 19666–71. doi:10.1073/pnas.0807826105. PMC 2605001. PMID 19066219. 
  29. ^ Zhu M, Li J, Fink AL (October 2003). "The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation". J. Biol. Chem. 278 (41): 40186–97. doi:10.1074/jbc.M305326200. PMID 12885775. 
  30. ^ Madine J, Doig AJ, Middleton DA (May 2006). "A study of the regional effects of alpha-synuclein on the organization and stability of phospholipid bilayers". Biochemistry 45 (18): 5783–92. doi:10.1021/bi052151q. PMID 16669622. 
  31. ^ Varkey J, Isas JM, Mizuno N, Jensen MB, Bhatia VK, Jao CC, Petrlova J, Voss J, Stamou D, Steven AC, Langen R (August 2010). "Membrane curvature induction and tubulation is a common feature of synucleins and apolipoproteins". J Biol Chem 285 (42): 32486–93. doi:10.1074/jbc.M110.139576. PMC 2952250. PMID 20693280. 
  32. ^ Remodeling of lipid vesicles into cylindrical micelles by α-synuclein in an extended α-helical conformation Naoko Mizuno, Jobin Varkey, Natalie C. Kegulian, Balachandra G. Hegde, Naiqian Cheng, Ralf Langen and Alasdair C. Steven
  33. ^ α-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles. Jobin Varkey, Naoko Mizuno, Balachandra G. Hegde, Naiqian Cheng, Alasdair C. Steven and Ralf Langen
  34. ^ Zhu M, Qin ZJ, Hu D, Munishkina LA, Fink AL (July 2006). "Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles". Biochemistry 45 (26): 8135–42. doi:10.1021/bi052584t. PMID 16800638. 
  35. ^ Clayton D.F. and George J.M. (1998). "The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease". Trends in Neuroscience 21 (6): 249–254. doi:10.1016/S0166-2236(97)01213-7. 
  36. ^ Vlad C, Lindner K, Karreman C, Schildknecht S, Leist M, Tomczyk N, Rontree J, Langridge J, Danzer K, Ciossek T, Petre A, Gross ML, Hengerer B, Przybylski M (December 2011). "Autoproteolytic fragments are intermediates in the oligomerization/aggregation of the Parkinson's disease protein alpha-synuclein as revealed by ion mobility mass spectrometry". Chembiochem 12 (18): 2740–4. doi:10.1002/cbic.201100569. PMC 3461308. PMID 22162214. 
  37. ^ Bartels T, Choi JG, Selkoe DJ (August 2011). "α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation". Nature 477 (7362): 107–10. doi:10.1038/nature10324. PMC 3166366. PMID 21841800. Lay summaryHarvard Medical School New Focus. 
  38. ^ Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997). "Alpha-synuclein in Lewy bodies.". Nature 388 (6645): 839–40. doi:10.1038/42166. PMID 9278044. 
  39. ^ Mezey E, Dehejia A, Harta G, Papp MI, Polymeropoulos MH, Brownstein MJ (1998). "Alpha synuclein in neurodegenerative disorders: murderer or accomplice?". Nat Med 4 (7): 755–7. doi:10.1038/nm0798-755. PMID 9662355. 
  40. ^ Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Uéda K, Ikeda K, Kawai M (October 1999). "Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies". Brain Res. 843 (1): 53–61. doi:10.1016/S0006-8993(99)01848-X. PMID 10528110. 
  41. ^ Arima K, Mizutani T, Alim MA, Tonozuka-Uehara H, Izumiyama Y, Hirai S, Uéda K (August 2000). "NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies". Acta Neuropathol. 100 (2): 115–21. doi:10.1007/s004010050002. PMID 10963357. 
  42. ^ Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Nakashima H, Yasuda M, Kitamura Y, Uéda K, Checler F, Kuroda S (December 2002). "NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases". Acta Neuropathol. 104 (6): 637–48. doi:10.1007/s00401-002-0596-7. PMID 12410385. 
  43. ^ Kim HY, Heise H, Fernandez CO, Baldus M, Zweckstetter M (September 2007). "Correlation of amyloid fibril beta-structure with the unfolded state of alpha-synuclein". Chembiochem 8 (14): 1671–4. doi:10.1002/cbic.200700366. PMID 17722123. 
  44. ^ Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, Musiani F, Brucale M, Bubacco L, Samorì B (January 2008). "Conformational equilibria in monomeric α-synuclein at the single-molecule level". PLoS Biol. 6 (1): e6. doi:10.1371/journal.pbio.0060006. PMC 2174973. PMID 18198943. 
  45. ^ Morshedi D, Aliakbari F, (Spring 2012). "The Inhibitory Effects of Cuminaldehyde on Amyloid Fibrillation and Cytotoxicity of Alpha-synuclein". modares journal of medical sciences: pathobiology 15 (1): 45–60. 
  46. ^ Woulfe J, Hoogendoorn H, Tarnopolsky M, Muñoz DG. (Nov 14, 2000). "Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain.". Neurology 55 (9): 1398–401. doi:10.1212/WNL.55.9.1398. PMID 11087792. 
  47. ^ Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. (1997). "Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.". Science 276 (5321): 2045–7. doi:10.1126/science.276.5321.2045. PMID 9197268. 
  48. ^ Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S et al. (1998). "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.". Nat Genet 18 (2): 106–8. doi:10.1038/ng0298-106. PMID 9462735. 
  49. ^ Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG (February 2004). "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia". Annals of Neurology 55 (2): 164–73. doi:10.1002/ana.10795. PMID 14755719. 
  50. ^ Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (October 2003). "alpha-Synuclein locus triplication causes Parkinson's disease". Science 302 (5646): 841. doi:10.1126/science.1090278. PMID 14593171. 
  51. ^ Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (Feb 2002). "alpha-Synuclein is phosphorylated in synucleinopathy lesions". Nat Cell Biol 4 (2): 160–164. doi:10.1038/ncb748. PMID 11813001. 
  52. ^ Cookson MR (2009). "alpha-Synuclein and neuronal cell death". Mol Neurodegener 4: 9. doi:10.1186/1750-1326-4-9. PMC 2646729. PMID 19193223. 
  53. ^ Takeda A, Hashimoto M, Mallory M, Sundsumo M, Hansen L, Masliah E (March 2000). "C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders". Acta Neuropathol. 99 (3): 296–304. doi:10.1007/PL00007441. PMID 10663973. 
  54. ^ Wersinger C, Sidhu A (April 2003). "Attenuation of dopamine transporter activity by alpha-synuclein". Neurosci. Lett. 340 (3): 189–92. doi:10.1016/S0304-3940(03)00097-1. PMID 12672538. 
  55. ^ Lee FJ, Liu F, Pristupa ZB, Niznik HB (April 2001). "Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis". FASEB J. 15 (6): 916–26. doi:10.1096/fj.00-0334com. PMID 11292651. 
  56. ^ Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM, Wolozin B (September 2001). "Co-association of parkin and alpha-synuclein". NeuroReport 12 (13): 2839–43. doi:10.1097/00001756-200109170-00017. PMID 11588587. 
  57. ^ Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E (March 2008). "alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease". J. Biol. Chem. 283 (11): 6979–87. doi:10.1074/jbc.M710418200. PMID 18195004. 
  58. ^ Ahn BH, Rhim H, Kim SY, Sung YM, Lee MY, Choi JY, Wolozin B, Chang JS, Lee YH, Kwon TK, Chung KC, Yoon SH, Hahn SJ, Kim MS, Jo YH, Min DS (April 2002). "alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells". J. Biol. Chem. 277 (14): 12334–42. doi:10.1074/jbc.M110414200. PMID 11821392. 
  59. ^ Neystat M, Rzhetskaya M, Kholodilov N, Burke RE (June 2002). "Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay". Neurosci. Lett. 325 (2): 119–23. doi:10.1016/S0304-3940(02)00253-7. PMID 12044636. 
  60. ^ Reed JC, Meister L, Tanaka S, Cuddy M, Yum S, Geyer C, Pleasure D (December 1991). "Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin". Cancer Res. 51 (24): 6529–38. PMID 1742726. 
  61. ^ Kawamata H, McLean PJ, Sharma N, Hyman BT (May 2001). "Interaction of alpha-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations". J. Neurochem. 77 (3): 929–34. doi:10.1046/j.1471-4159.2001.00301.x. PMID 11331421. 
  62. ^ Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA (May 1999). "Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions". Nat. Genet. 22 (1): 110–4. doi:10.1038/8820. PMID 10319874. 
  63. ^ Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (September 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 (36): 25481–9. doi:10.1074/jbc.274.36.25481. PMID 10464279. 
  64. ^ Giasson BI, Lee VM, Trojanowski JQ (2003). "Interactions of amyloidogenic proteins". Neuromolecular Med. 4 (1-2): 49–58. doi:10.1385/NMM:4:1-2:49. PMID 14528052. 
  65. ^ Ono, Kenjiro; Takahashi, Ryoichi; Ikedia, Tokuhei; Yamada, Masahito (2012). "Cross-seeding effects of amyloid β-protein and α-synuclein". Journal of Neurochemistry 122 (5): 883–90. doi:10.1111/j.1471-4159.2012.07847.x. PMID 22734715. Retrieved 13 February 2013. 

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