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). Voltage-activated complexation of alpha-synuclein with three beta-barrel channels: VDAC, MspA, and alpha-hemolysin has been demonstrated (Hoogerheide et al. 2021).

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).

VDAC provides the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane (Rostovtseva et al. 2021). VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two   cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. The features of the VDAC gated states relevant to reduced metabolite flux and increased calcium flux are preserved in the blocked state induced by either docking protein (Rostovtseva et al. 2021).

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 (<Rostovtseva et al. 2021). VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two   cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. The features of the VDAC gated states relevant to reduced metabolite flux and increased calcium flux are preserved in the blocked state induced by either docking protein (Rostovtseva et al. 2021).

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 (<Rostovtseva et al. 2021).

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).