Editing Alpha-synuclein (section)

=== 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>