Alpha-synuclein

































































SNCA
Alfa-sinucleina.jpg







Available structures
PDB Ortholog search: PDBe RCSB



Identifiers
Aliases
SNCA, NACP, PARK1, PARK4, PD1, synuclein alpha
External IDs OMIM: 163890 MGI: 1277151 HomoloGene: 293 GeneCards: SNCA


















Gene location (Human)
Chromosome 4 (human)
Chr. Chromosome 4 (human)[1]

Chromosome 4 (human)
Genomic location for SNCA

Genomic location for SNCA

Band 4q22.1 Start 89,724,099 bp[1]
End 89,838,315 bp[1]























RNA expression pattern

PBB GE SNCA 204466 s at fs.png

PBB GE SNCA 204467 s at fs.png
More reference expression data















Orthologs
Species Human Mouse
Entrez


6622


20617
Ensembl


ENSG00000145335


ENSMUSG00000025889
UniProt


P37840


O55042
RefSeq (mRNA)


NM_000345
NM_001146054
NM_001146055
NM_007308


NM_001042451
NM_009221
RefSeq (protein)


NP_000336
NP_001139526
NP_001139527
NP_009292


NP_001035916
NP_033247
Location (UCSC) Chr 4: 89.72 – 89.84 Mb Chr 6: 60.73 – 60.83 Mb

PubMed search		 [3] [4]
Wikidata



View/Edit Human View/Edit Mouse

Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene.[5] It is abundant in the brain while smaller amounts are found in the heart, muscles, and other tissues. In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals.[5] Within these structures, alpha-synuclein interacts with phospholipids[6] and proteins.[5] 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.[5]


Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in maintaining a supply of synaptic vesicles in presynaptic terminals by clustering synaptic vesicles.[7] 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.[5]


The human alpha-synuclein protein is made of 140 amino acids and is encoded by the SNCA gene.[8][9][10] 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.[8] It was later determined that NACP was the human homologue of Torpedo synuclein. Therefore, NACP is now referred to as human alpha-synuclein.




Contents






  • 1 Tissue expression


  • 2 Structure


  • 3 Function


    • 3.1 Interaction with lipid membranes




  • 4 Sequence


  • 5 Autoproteolytic activity


  • 6 Clinical significance


  • 7 Protein-protein interactions


  • 8 See also


  • 9 References


  • 10 Further reading


  • 11 External links





Tissue expression


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.[11] 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.[12]


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.[13] Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms,[14] with roughly 15% of synuclein being membrane-bound in any moment in neurons.[15]


It has also been shown that alpha-synuclein is localized in neuronal mitochondria.[16][17] 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.[17]


At least three isoforms of synuclein are produced through alternative splicing.[18] The majority form of the protein, and the one most investigated, is the full-length protein of 140 amino acids. Other isoforms are alpha-synuclein-126, which lacks residues 41-54 due to loss of exon 3; and alpha-synuclein-112,[19] which lacks residue 103-130 due to loss of exon 5.[18]



Structure


Alpha-synuclein in solution is considered to be an intrinsically disordered protein, i.e. it lacks a single stable 3D structure.[20] 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.[21]



Function


Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.[22]
It has been shown that alpha-synuclein significantly interacts with tubulin,[23] and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau.[24]


Recent evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes.[25][26] 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.[27] Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.[28]


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.[29]



Interaction with lipid membranes


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.[30] Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.[31]


Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids.[31] Alpha-synuclein forms an extended helical structure on small unilamellar vesicles.[32] A preferential binding to small vesicles has been found.[33] 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.[34] Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.[35] Using cryo-EM it was shown that these are micellar tubes of ~5-6 nm diameter.[36] Alpha-synuclein has also been shown to form lipid disc-like particles similar to apolipoproteins.[37] EPR studies have shown that the structure of alpha synuclein is dependent on the binding surface.[38] The protein adopts a broken-helical conformation on lipoprotein particles while it forms an extended helical structure on lipid vesicles and membrane tubes.[38] Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane.[39]




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


Membrane interaction of alpha-synuclein modulates or affects its rate of aggregation.[40] The membrane-mediated modulation of aggregation is very similar to that observed for other amyloid proteins such as IAPP and abeta.[40] Aggregated states of alpha-synuclein permeate the membrane of lipid vesicles.[41] They are formed upon interaction with peroxidation-prone polyunsaturated fatty acids (PUFA) but not with monounsaturated fatty acids[42] and the binding of lipid autoxidation-promoting transition metals such as iron or copper provokes oligomerization of alpha-synuclein.[43] The aggregated alpha-synuclein has a specific activity for peroxidized lipids and induces lipid autoxidation in PUFA-rich membranes of both neurons and astrocytes, decreasing resistance to apoptosis.[44] Lipid autoxidation is inhibited if the cells are pre-incubated with isotope-reinforced PUFAs (D-PUFA).[45]



Sequence


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[46]

  • Residues 61-95: A central hydrophobic region which includes the non-amyloid-β component (NAC) region, involved in protein aggregation[8]

  • Residues 96-140: a highly acidic and proline-rich region which has no distinct structural propensity



Autoproteolytic activity


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.[47] 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




Positive α-Synuclein staining of a Lewy body from a patient who had Parkinson's disease.


Classically considered an unstructured soluble protein, unmutated α-synuclein forms a stably folded tetramer that resists aggregation.[48] This observation, though reproduced and extended by several labs,[49][50][51] is still a matter of debate in the field due to conflicting reports.[52][53][54] 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.[55][56] These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein;[57] however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.[58] Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.[59]


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.[60] 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.[61] One theory is that the majority of alpha-synuclein aggregates are located in the presynapse as smaller deposits which causes synaptic dysfunction.[62] 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.[63]
The Epstein-Barr virus has been implicated in these disorders.[64]


In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. Five point mutations have been identified thus far: A53T,[65] A30P,[66] E46K,[67] H50Q,[68] and G51D.[69] It has been reported that some mutations influence the initiation and amplification steps of the aggregation process.[70] 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.[71] Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease.


Certain sections of the alpha-synuclein protein may play a role in the tauopathies.[72]


A prion form of the protein alpha-synuclein may be a causal agent for the disease multiple system atrophy.[73][74][75]




Events in α-synuclein toxicity.[76]


Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies.[77] The central panel in the figure to the right 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.



Protein-protein interactions


Alpha-synuclein has been shown to interact with




  • Dopamine transporter,[78][79]


  • Parkin (ligase),[80][81]


  • Phospholipase D1,[82]


  • SNCAIP,[83][84][85][86]


  • Tau protein.[87][88]


  • Beta amyloid[89]



See also



  • Synuclein


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



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Further reading


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  • Blakeslee S (2002-05-27). "In Folding Proteins, Clues to Many Diseases -". New York Times.


  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (June 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.


  • 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 (November 2002). "Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies". The Journal of Clinical Investigation. 110 (10): 1429–39. doi:10.1172/JCI15777. PMC 151810. PMID 12438441.


  • George JM (2001). "The synucleins". Genome Biology. 3 (1): REVIEWS3002. doi:10.1186/gb-2001-3-1-reviews3002. PMC 150459. PMID 11806835.


  • Lavedan C (September 1998). "The synuclein family". Genome Research. 8 (9): 871–80. doi:10.1101/gr.8.9.871. PMID 9750188.


  • Ozawa T, Wakabayashi K, Oyanagi K (February 2002). "[Recent progress in the research of multiple system atrophy with special references to alpha-synuclein and suprachiasmatic nucleus]". No to Shinkei = Brain and Nerve. 54 (2): 111–7. PMID 11889756.


  • Cole NB, Murphy DD (2002). "The cell biology of alpha-synuclein: a sticky problem?". Neuromolecular Medicine. 1 (2): 95–109. doi:10.1385/NMM:1:2:95. PMID 12025860.


  • Iwatsubo T (June 2002). "[alpha-synuclein and Parkinson's disease]". Seikagaku. The Journal of Japanese Biochemical Society. 74 (6): 477–82. PMID 12138709.


  • Trojanowski JQ, Lee VM (October 2002). "Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses". Neurotoxicology. 23 (4–5): 457–60. doi:10.1016/S0161-813X(02)00065-7. PMID 12428717.


  • Alves da Costa C (February 2003). "Recent advances on alpha-synuclein cell biology: functions and dysfunctions". Current Molecular Medicine. 3 (1): 17–24. doi:10.2174/1566524033361690. PMID 12558071.


  • Ma QL, Chan P, Yoshii M, Uéda K (April 2003). "Alpha-synuclein aggregation and neurodegenerative diseases". Journal of Alzheimer's Disease. 5 (2): 139–48. PMID 12719631.


  • Di Rosa G, Puzzo D, Sant'Angelo A, Trinchese F, Arancio O (October 2003). "Alpha-synuclein: between synaptic function and dysfunction". Histology and Histopathology. 18 (4): 1257–66. doi:10.14670/HH-18.1257. PMID 12973692.


  • Baptista MJ, Cookson MR, Miller DW (February 2004). "Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease". The Neuroscientist. 10 (1): 63–72. doi:10.1177/1073858403260392. PMID 14987449.


  • Kim S, Seo JH, Suh YH (May 2004). "Alpha-synuclein, Parkinson's disease, and Alzheimer's disease". Parkinsonism & Related Disorders. 10 Suppl 1: S9–13. doi:10.1016/j.parkreldis.2003.11.005. PMID 15109581.


  • Sidhu A, Wersinger C, Vernier P (May 2004). "alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease". FEBS Letters. 565 (1–3): 1–5. doi:10.1016/j.febslet.2004.03.063. PMID 15135042.


  • Vekrellis K, Rideout HJ, Stefanis L (August 2004). "Neurobiology of alpha-synuclein". Molecular Neurobiology. 30 (1): 1–21. doi:10.1385/MN:30:1:001. PMID 15247485.


  • Chiba-Falek O, Nussbaum RL (2004). "Regulation of alpha-synuclein expression: implications for Parkinson's disease". Cold Spring Harbor Symposia on Quantitative Biology. 68: 409–15. doi:10.1101/sqb.2003.68.409. PMID 15338643.


  • Pankratz N, Foroud T (April 2004). "Genetics of Parkinson disease". NeuroRx. 1 (2): 235–42. doi:10.1602/neurorx.1.2.235. PMC 534935. PMID 15717024.


  • Singleton AB (August 2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin". Trends in Neurosciences. 28 (8): 416–21. doi:10.1016/j.tins.2005.05.009. PMID 15955578.


  • Yu S, Uéda K, Chan P (2005). "Alpha-synuclein and dopamine metabolism". Molecular Neurobiology. 31 (1–3): 243–54. doi:10.1385/MN:31:1-3:243. PMID 15953825.


  • Lee HG, Zhu X, Takeda A, Perry G, Smith MA (July 2006). "Emerging evidence for the neuroprotective role of alpha-synuclein". Experimental Neurology. 200 (1): 1–7. doi:10.1016/j.expneurol.2006.04.024. PMID 16780837.


  • Giorgi FS, Bandettini di Poggio A, Battaglia G, Pellegrini A, Murri L, Ruggieri S, Paparelli A, Fornai F (2006). "A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson's disease". Journal of Neural Transmission. Supplementum. 70 (70): 105–9. doi:10.1007/978-3-211-45295-0_17. PMID 17017516.




External links




  • Media related to alpha synuclein at Wikimedia Commons


  • alpha-Synuclein at the US National Library of Medicine Medical Subject Headings (MeSH)

  • Human SNCA genome location and SNCA gene details page in the UCSC Genome Browser.









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章鱼与海女图

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本条目 可参照英語維基百科相應條目来扩充 。 （2014/5/25） 若您熟悉来源语言和主题，请协助参考外语维基扩充条目。请勿直接提交机械翻译，也不要翻译不可靠、低品质内容。依版权协议，译文需在编辑摘要注明来源，或于讨论页顶部标记 {{Translated page}} 标签。 本条目 需要擴充。 （2013年8月15日） 请協助改善这篇條目，更進一步的信息可能會在討論頁或扩充请求中找到。请在擴充條目後將此模板移除。 《 章鱼与海女 》（日语： 蛸と海女 ／ たことあま   Tako to ama ）是一幅由日本畫家葛饰北斋创作的浮世绘，出自1814年（文化4年）出版的艳本《喜能会之故真通》（日语： 喜能会之故真通 ／ きのえのこまつ   Kinoe no Komatsu ）。畫中有兩隻章鱼以觸手攻擊一名採珠的海女，並進行擬似戀獸癖的交媾行為。作品尺寸为6½" × 8¾" （16.51 cm × 22.23 cm）。 [1] 在此之前的类似作品还有北尾重政的艳本《謡曲色番組》及勝川春潮的艳本《艳本千夜多女志》等，有被北斋作为参考的可能性。 《章鱼与海女图》有不同英文翻译，一般称The Dream of the Fisherman's Wife，又作Girl Diver and Octopi、Diver and Two Octopi，Richard Douglas Lane称其为 Girl Diver and Octopi [2] ，Mathi Forrer 称其为 Pearl Diver and Two Octopi [3] ，Danielle Talerico 称其为 Diver and Two Octopi 。 [4] 目录 1 作品介绍 1.1 画中对话 1.2 解释 2 评价 3 影响 3.1 模仿作品 4 另见 5 参考来源 6 外部連結 作品介绍 画中对话 原文 译文 大蛸： いつぞハいつぞハとねらいすましてゐたかいがあつて、けふといふけふ、とうとうとらまへたア。てもむつくりとしたいいぼぼだ。いもよりハなをこうぶつだ。サアサア、すつてすつてすいつくして...
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