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1.C.77 The Synuclein (Synuclein) Family

α-Synuclein is a cytreolic protein in neurons that when mutated promotes Parkinson's disease (PD) (Waxman and Giasson, 2009). In solution it is disordered, but in membranes it forms amphipathic helices. Three mutations in synuclein (A30P, E46K and A53T) give rise to PD. Like other cytotoxic amylins (TC #1.C.49), synuclein forms channels in artificial and biological membranes, and the mutations that promote early onset PD alter channel formation (Caughey and Lansbury, 2003; Fredenburg et al., 2007; Rochet et al., 2004). Altered ion channel formation by the Parkinson's-diesease-linked E46K mutant of alpha-synuclein is corrected by GM3 but not by GM1 gangliosides (Di Pasquale et al., 2010). Homologues are found in animals including C. elegans. Sequence similarity is observed for late embryogenesis abundant proteins (e.g., ABE88565) of Medicago truncatula and the Dauer up-regulated (Dur-1) proteins of C. elegans. Synucleins and their homologues contain an 11-residue repeat unit of sequence: KTKEGVVX4 (occurring 5 times from residue 10 to residue 68 in α-synuclein). The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast (Vamvaca et al., 2009).

α-Synuclein is a cystolic protein that is disordered in an aqueous enviroment but develops a highly helical conformation when bound to membranes having a negatively charged surface and a large curvature. It exhibits a membrane-permeabilizing activity that has been attributed to oligomeric protofibrillar forms. Monomeric wild-type α-Synuclein and two mutants associated with familial PD, E46K and A53T, formed ion channels with well-defined conductance states in membranes with a trans-negative potential (Zakharov et al., 2007). Another familial mutant, A30P, known to have a lower membrane affinity, did not form ion channels. Ca2 prevented channel formation when added to membranes before α-Synuclein and decreased channel conductance when added to preformed channels. In contrast to the monomer, membrane permeabilization by oligomeric α-Synuclein was not characterized by formation of discrete channels. Thus, discrete ion channels with well-defined conductance states were formed in the presence of a membrane potential by one or several moleules of monomeric α-Synuclein in an alpha-helical conformation. Such channels may have a role in the normal function and/orpathophysiology of the protein (Zakharov et al., 2007).

Another study suggested that a distinct transmembrane pore complex formed not by monomers, but by synuclein oligomers. In this case, pore formation was inhibited by co-incubation with the aggregation inhibitor, baicalein (Schmidt et al. 2012). Aberrant accumulation of α- and β-synuclein in degradative organelles are features of presenilin-1 -/- neurons, and similar events may promote the formation of alpha-synuclein inclusions associated with neurodegenerative diseases (Wilson et al. 2004). Cyclophilin D binds to the acidic C-terminal region of alpha-Synuclein and affects its aggregation characteristics (Torpey et al. 2020).

References associated with 1.C.77 family:

Angelova, P.R., M.H. Ludtmann, M.H. Horrocks, A. Negoda, N. Cremades, D. Klenerman, C.M. Dobson, N.W. Wood, E.V. Pavlov, S. Gandhi, and A.Y. Abramov. (2016). Ca2+ is a key factor in α-synuclein-induced neurotoxicity. J Cell Sci 129: 1792-1801. 26989132
Caughey, B. and P.T. Lansbury. (2003). Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26: 267-298. 12704221
Di Pasquale, E., J. Fantini, H. Chahinian, M. Maresca, N. Taïeb, and N. Yahi. (2010). Altered ion channel formation by the Parkinson's-disease-linked E46K mutant of α-synuclein is corrected by GM3 but not by GM1 gangliosides. J. Mol. Biol. 397: 202-218. 20114052
Fredenburg, R.A., C. Rospigliosi, R.K. Meray, J.C. Kessler, H.A. Lashuel, D. Eliezer, and P.T. Lansbury. (2007). The Impact of the E46K mutation on the properties of α-synuclein in its monomeric and oligomeric states. Biochemistry 46: 7107-7118. 17530780
Gurnev, P.A., T.L. Yap, C.M. Pfefferkorn, T.K. Rostovtseva, A.M. Berezhkovskii, J.C. Lee, V.A. Parsegian, and S.M. Bezrukov. (2014). Alpha-synuclein lipid-dependent membrane binding and translocation through the α-hemolysin channel. Biophys. J. 106: 556-565. 24507596
Liu, C., L. Qu, and C. Shou. (2016). Role and Characterization of Synuclein-γ Unconventional Protein Secretion in Cancer Cells. Methods Mol Biol 1459: 215-227. 27665562
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Rochet, J.C., T.F. Outeiro, K.A. Conway, T.T. Ding, M.J. Volles, H.A. Lashuel, R.M. Bieganski, S.L. Lindquist, and P.T. Lansbury. (2004). Interactions among α-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease. J. Mol. Neurosci. 23: 23-34. 15126689
Schmidt, F., J. Levin, F. Kamp, H. Kretzschmar, A. Giese, and K. Bötzel. (2012). Single-Channel Electrophysiology Reveals a Distinct and Uniform Pore Complex Formed by α-Synuclein Oligomers in Lipid Membranes. PLoS One 7: e42545. 22880029
Torpey, J., J. Madine, A. Wood, and L.Y. Lian. (2020). Cyclophilin D binds to the acidic C-terminus region of α-Synuclein and affects its aggregation characteristics. Sci Rep 10: 10159. 32576835
Urrea, L., I. Ferrer, R. Gavín, and J.A. Del Río. (2017). The cellular prion protein (PrPC) as neuronal receptor for α-synuclein. Prion 11: 226-233. 28759332
Vamvaca, K., M.J. Volles, and P.T. Lansbury, Jr. (2009). The first N-terminal amino acids of α-synuclein are essential for α-helical structure formation in vitro and membrane binding in yeast. J. Mol. Biol. 389: 413-424. 19285989
Waxman, E.A. and B.I. Giasson. (2009). Molecular mechanisms of α-synuclein neurodegeneration. Biochim. Biophys. Acta. 1792: 616-624. 18955133
Wilson, C.A., D.D. Murphy, B.I. Giasson, B. Zhang, J.Q. Trojanowski, and V.M. Lee. (2004). Degradative organelles containing mislocalized α-and β-synuclein proliferate in presenilin-1 null neurons. J. Cell Biol. 165: 335-346. 15123735
Yang, J.H. and E.S. Choe. (2014). Protein kinase G regulates β-synuclein in response to repeated exposure to cocaine in the rat dorsal striatum in a Ca²⁺-dependent manner. Neurosci Lett 582: 6-11. 25181031
Zakharov, S.D., J.D. Hulleman, E.A. Dutseva, Y.N. Antonenko, J.C. Rochet, and W.A. Cramer. (2007). Helical α- synuclein forms highly conductive ion channels. Biochemistry 46: 14369-14379. 18031063