Editing Alpha-synuclein (section)

== Structure ==

Alpha-synuclein in solution is considered to be an [[intrinsically disordered protein]], i.e. it lacks a single stable 3D structure.<ref name="van_Rooijen_2009">{{cite journal | vauthors = van Rooijen BD, van Leijenhorst-Groener KA, Claessens MM, Subramaniam V | title = Tryptophan fluorescence reveals structural features of alpha-synuclein oligomers | journal = Journal of Molecular Biology | volume = 394 | issue = 5 | pages = 826–833 | date = December 2009 | pmid = 19837084 | doi = 10.1016/j.jmb.2009.10.021 | s2cid = 36085937 | url = https://ris.utwente.nl/ws/files/6758594/Rooijen09tryptophan.pdf }}</ref><ref>{{cite journal | vauthors = Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT | title = NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded | journal = Biochemistry | volume = 35 | issue = 43 | pages = 13709–13715 | date = October 1996 | pmid = 8901511 | doi = 10.1021/bi961799n }}</ref> 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 [[protein dimer|dimer]]s or [[tetramer]]s of alpha-synuclein.<ref name="Neupane_2014">{{cite journal | vauthors = Neupane K, Solanki A, Sosova I, Belov M, Woodside MT | title = Diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e86495 | date = January 2014 | pmid = 24475132 | pmc = 3901707 | doi = 10.1371/journal.pone.0086495 | doi-access = free | bibcode = 2014PLoSO...986495N }}</ref>

Alpha-synuclein is specifically [[Regulation of gene expression|upregulated]] in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.<ref name="George_1995">{{cite journal | vauthors = George JM, Jin H, Woods WS, Clayton DF | title = Characterization of a novel protein regulated during the critical period for song learning in the zebra finch | journal = Neuron | volume = 15 | issue = 2 | pages = 361–372 | date = August 1995 | pmid = 7646890 | doi = 10.1016/0896-6273(95)90040-3 | s2cid = 11421888 | doi-access = free }}</ref> It has been shown that alpha-synuclein significantly interacts with [[tubulin]],<ref name="Alim_2002">{{cite journal | vauthors = Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K | title = Tubulin seeds alpha-synuclein fibril formation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 3 | pages = 2112–2117 | date = January 2002 | pmid = 11698390 | doi = 10.1074/jbc.M102981200 | s2cid = 84374030 | doi-access = free }}</ref> and that alpha-synuclein may have activity as a potential [[microtubule-associated protein]], like [[Tau protein|tau]].<ref name="Alim_2004">{{cite journal | vauthors = Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, Hisanaga S, Uéda K | title = Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein | journal = Journal of Alzheimer's Disease | volume = 6 | issue = 4 | pages = 435–42; discussion 443–9 | date = August 2004 | pmid = 15345814 | doi = 10.3233/JAD-2004-6412 }}</ref> Evidence suggests that alpha-synuclein functions as a [[molecular chaperone]] in the formation of [[SNARE (protein)|SNARE]] complexes.<ref name="Bonini_2005">{{cite journal | vauthors = Bonini NM, Giasson BI | title = Snaring the function of alpha-synuclein | journal = Cell | volume = 123 | issue = 3 | pages = 359–361 | date = November 2005 | pmid = 16269324 | doi = 10.1016/j.cell.2005.10.017 | s2cid = 18772904 | doi-access = free }}</ref><ref name="Chandra_2005">{{cite journal | vauthors = Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC | title = Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration | journal = Cell | volume = 123 | issue = 3 | pages = 383–396 | date = November 2005 | pmid = 16269331 | doi = 10.1016/j.cell.2005.09.028 | s2cid = 18173864 | doi-access = free }}</ref> 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.<ref name="Burre_2010">{{cite journal | vauthors = Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC | title = Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro | journal = Science | location = New York, N.Y. | volume = 329 | issue = 5999 | pages = 1663–1667 | date = September 2010 | pmid = 20798282 | pmc = 3235365 | doi = 10.1126/science.1195227 | bibcode = 2010Sci...329.1663B }}</ref> Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal [[Golgi apparatus]] and [[Vesicle (biology)|vesicle]] trafficking.<ref name="Cooper_2006">{{cite journal | vauthors = Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S | title = Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models | journal = Science | location = New York, N.Y. | volume = 313 | issue = 5785 | pages = 324–328 | date = July 2006 | pmid = 16794039 | pmc = 1983366 | doi = 10.1126/science.1129462 | bibcode = 2006Sci...313..324C }}</ref>

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.<ref name="Kokhan_2012">{{cite journal | vauthors = Kokhan VS, Afanasyeva MA, Van'kin GI | title = α-Synuclein knockout mice have cognitive impairments | journal = Behavioural Brain Research | volume = 231 | issue = 1 | pages = 226–230 | date = May 2012 | pmid = 22469626 | doi = 10.1016/j.bbr.2012.03.026 | s2cid = 205884600 }}</ref>

=== Interaction with lipid membranes ===

Experimental evidence has been collected on the interaction of alpha-synuclein with [[cell membrane|membrane]] and its involvement with membrane composition and turnover. [[Saccharomyces cerevisiae|Yeast]] genome screening has found that several genes that deal with lipid metabolism and mitochondrial fusion play a role in alpha-synuclein toxicity.<ref>{{cite journal | vauthors = Tauro M | title = Alpha-Synuclein Toxicity is Caused by Mitochondrial Dysfunction | journal = Electronic Thesis and Dissertation Repository | date = 4 February 2019 | url = https://ir.lib.uwo.ca/etd/6019 }}</ref><ref name="Willingham_2003">{{cite journal | vauthors = Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ | title = Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein | journal = Science | location = New York, N.Y. | volume = 302 | issue = 5651 | pages = 1769–1772 | date = December 2003 | pmid = 14657499 | doi = 10.1126/science.1090389 | s2cid = 43221047 | bibcode = 2003Sci...302.1769W }}</ref> Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.<ref name="Uversky_2007">{{cite journal | vauthors = Uversky VN | title = Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation | journal = Journal of Neurochemistry | volume = 103 | issue = 1 | pages = 17–37 | date = October 2007 | pmid = 17623039 | doi = 10.1111/j.1471-4159.2007.04764.x | s2cid = 85334400 }}</ref>

Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of [[phospholipids]].<ref name="Uversky_2007" /> Alpha-synuclein forms an extended helical structure on small unilamellar vesicles.<ref name="Jao_2008">{{cite journal | vauthors = Jao CC, Hegde BG, Chen J, Haworth IS, Langen R | title = Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 50 | pages = 19666–19671 | date = December 2008 | pmid = 19066219 | pmc = 2605001 | doi = 10.1073/pnas.0807826105 | doi-access = free | bibcode = 2008PNAS..10519666J }}</ref> A preferential binding to small vesicles has been found.<ref name="Zhu_2003">{{cite journal | vauthors = Zhu M, Li J, Fink AL | title = The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 40186–40197 | date = October 2003 | pmid = 12885775 | doi = 10.1074/jbc.M305326200 | s2cid = 41555488 | doi-access = free }}</ref> 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.<ref name="Madine_2006">{{cite journal | vauthors = Madine J, Doig AJ, Middleton DA | title = A study of the regional effects of alpha-synuclein on the organization and stability of phospholipid bilayers | journal = Biochemistry | volume = 45 | issue = 18 | pages = 5783–5792 | date = May 2006 | pmid = 16669622 | doi = 10.1021/bi052151q }}</ref> Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.<ref name="Varkey_2010">{{cite journal | vauthors = Varkey J, Isas JM, Mizuno N, Jensen MB, Bhatia VK, Jao CC, Petrlova J, Voss JC, Stamou DG, Steven AC, Langen R | title = Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins | journal = The Journal of Biological Chemistry | volume = 285 | issue = 42 | pages = 32486–32493 | date = October 2010 | pmid = 20693280 | pmc = 2952250 | doi = 10.1074/jbc.M110.139576 | doi-access = free }}</ref> Using [[cryo-EM]] it was shown that these are micellar tubes of ~5-6&nbsp;nm diameter.<ref name="Mizuno_2012">{{cite journal | vauthors = Mizuno N, Varkey J, Kegulian NC, Hegde BG, Cheng N, Langen R, Steven AC | title = Remodeling of lipid vesicles into cylindrical micelles by α-synuclein in an extended α-helical conformation | journal = The Journal of Biological Chemistry | volume = 287 | issue = 35 | pages = 29301–29311 | date = August 2012 | pmid = 22767608 | pmc = 3436199 | doi = 10.1074/jbc.M112.365817 | doi-access = free }}</ref> Alpha-synuclein has also been shown to form lipid disc-like particles similar to [[apolipoproteins]].<ref name="Varkey_2013">{{cite journal | vauthors = Varkey J, Mizuno N, Hegde BG, Cheng N, Steven AC, Langen R | title = α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles | journal = The Journal of Biological Chemistry | volume = 288 | issue = 24 | pages = 17620–17630 | date = June 2013 | pmid = 23609437 | pmc = 3682563 | doi = 10.1074/jbc.M113.476697 | doi-access = free }}</ref> EPR studies have shown that the structure of alpha synuclein is dependent on the binding surface.<ref name="Varkey J 2017">{{cite journal | vauthors = Varkey J, Langen R | title = Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR | journal = Journal of Magnetic Resonance | location = San Diego, Calif. | volume = 280 | pages = 127–139 | date = July 2017 | pmid = 28579098 | pmc = 5461824 | doi = 10.1016/j.jmr.2017.02.014 | bibcode = 2017JMagR.280..127V }}</ref> The protein adopts a broken-helical conformation on lipoprotein particles while it forms an extended helical structure on lipid vesicles and membrane tubes.<ref name="Varkey J 2017"/> Studies have also suggested a possible [[antioxidant]] activity of alpha-synuclein in the membrane.<ref name="Zhu_2006">{{cite journal | vauthors = Zhu M, Qin ZJ, Hu D, Munishkina LA, Fink AL | title = Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles | journal = Biochemistry | volume = 45 | issue = 26 | pages = 8135–8142 | date = July 2006 | pmid = 16800638 | doi = 10.1021/bi052584t }}</ref> 
[[File:Lewy bodies (alpha synuclein inclusions).svg|right|thumb|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.<ref name="Rawat A 2018">{{cite journal | vauthors = Rawat A, Langen R, Varkey J | title = Membranes as modulators of amyloid protein misfolding and target of toxicity | journal = Biochimica et Biophysica Acta. Biomembranes | volume = 1860 | issue = 9 | pages = 1863–1875 | date = September 2018 | pmid = 29702073 | pmc = 6203680 | doi = 10.1016/j.bbamem.2018.04.011 }}</ref> The membrane-mediated modulation of aggregation is very similar to that observed for other amyloid proteins such as IAPP and abeta.<ref name="Rawat A 2018"/> Aggregated states of alpha-synuclein permeate the membrane of lipid vesicles.<ref>{{cite journal | vauthors = Flagmeier P, De S, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, Knowles TP, Gandhi S, Dobson CM, Klenerman D | title = Ultrasensitive Measurement of Ca<sup>2+</sup> Influx into Lipid Vesicles Induced by Protein Aggregates | journal = Angewandte Chemie | location = International Ed. in English | volume = 56 | issue = 27 | pages = 7750–7754 | date = June 2017 | pmid = 28474754 | pmc = 5615231 | doi = 10.1002/anie.201700966 }}</ref> They are formed upon interaction with peroxidation-prone [[polyunsaturated fatty acid]]s (PUFA) but not with [[monounsaturated fatty acid]]s<ref>{{cite journal | vauthors = Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ | title = The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease | journal = Neuron | volume = 37 | issue = 4 | pages = 583–595 | date = February 2003 | pmid = 12597857 | doi = 10.1016/s0896-6273(03)00024-2 | s2cid = 1604719 | doi-access = free }}</ref> and the binding of lipid [[autoxidation]]-promoting [[transition metal]]s such as [[iron]] or [[copper]] provokes oligomerization of alpha-synuclein.<ref>{{cite journal | vauthors = Amer DA, Irvine GB, El-Agnaf OM | title = Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders | journal = Experimental Brain Research | volume = 173 | issue = 2 | pages = 223–233 | date = August 2006 | pmid = 16733698 | doi = 10.1007/s00221-006-0539-y | s2cid = 24760126 }}</ref> 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.<ref>{{cite journal | vauthors = Ruipérez V, Darios F, Davletov B | title = Alpha-synuclein, lipids and Parkinson's disease | journal = Progress in Lipid Research | volume = 49 | issue = 4 | pages = 420–428 | date = October 2010 | pmid = 20580911 | doi = 10.1016/j.plipres.2010.05.004 }}</ref> Lipid autoxidation is inhibited if the cells are pre-incubated with [[Deuterated drug|isotope-reinforced]] PUFAs (D-PUFA).<ref>{{cite journal | vauthors = Angelova PR, Horrocks MH, Klenerman D, Gandhi S, Abramov AY, Shchepinov MS | title = Lipid peroxidation is essential for α-synuclein-induced cell death | journal = Journal of Neurochemistry | volume = 133 | issue = 4 | pages = 582–589 | date = May 2015 | pmid = 25580849 | pmc = 4471127 | doi = 10.1111/jnc.13024 }}</ref>