GM1 Specifically Interacts with α-Synuclein and Inhibits Fibrillation

Abstract

The aggregation of alpha-synuclein is believed to be a key step in the etiology of Parkinson's disease. Alpha-synuclein is found in the cytosol and is associated with membranes in the presynaptic region of neurons and has recently been reported to be associated with lipid rafts and caveolae. We examined the interactions between several brain sphingolipids and alpha-synuclein and found that alpha-synuclein specifically binds to ganglioside GM1-containing small unilamellar vesicles (SUVs). This results in the induction of substantial alpha-helical structure and inhibition or elimination of alpha-synuclein fibril formation, depending on the amount of GM1 present. SUVs containing total brain gangliosides, gangliosides GM2 or GM3, or asialo-GM1 had weak inhibitory effects on alpha-synuclein fibrillation and induced some alpha-helical structure, while all other sphingolipids studied showed negligible interaction with alpha-synuclein. alpha-Synuclein binding to GM1-containing SUVs was accompanied by formation of oligomers of alpha-synuclein. The familial mutant A53T alpha-synuclein interacted with GM1-containing SUVs in an analogous manner to wild type, whereas the A30P mutant showed minimal interaction. This is the first detailed report showing a direct association between GM1 and alpha-synuclein, which is attributed to specific interaction between helical alpha-synuclein and both the sialic acid and carbohydrate moieties of GM1. The recruitment of alpha-synuclein by GM1 to caveolae and lipid raft regions in membranes could explain alpha-synuclein's localization to presynaptic membranes and raises the possibility that perturbation of GM1/raft association could induce changes in alpha-synuclein that contribute to the pathogenesis of PD.

Dopamine Transporter Activity Is Modulated by α-Synuclein

“…Recently, Cremona et al (55) have shown that localization of the transporter in the cholesterol-rich membrane raft microdomains is essential for the AMPH-induced reversed transport of dopamine in dopaminergic neurons. GM1 (monosialotetrahexosylganglioside) is a well characterized membrane ganglioside that is distributed in the cholesterol-enriched membrane microdomains (56) and has been show to interact with and recruit ␣-synuclein to membrane rafts (57). We used confocal microscopy to examine the hypothesis that elevated ␣-synuclein affects the membrane microdomain distribution of DAT to regulate its activity.…”

α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling

“…␣-Syn interacts with phospholipid membranes and particularly with acidic phospholipids, a phenomenon attributed to the electrostatic attractions with the lysine residues found in the N-terminal region of the protein (17). Furthermore, ␣-Syn has been reported to associate with lipid rafts, lipid domains enriched in cholesterol and sphingomyelin, as well as with gangliosides (18,19). It has been shown that ␣-Syn binds small (20 -25-nm) unilamellar vesicles in preference to larger (125-nm) vesicles of a given composition (17).…”

A deadly spread: cellular mechanisms of α-synuclein transfer

“…Interaction of a-syn with the ganglioside GM1, an essential component of the lipid rafts, has been proposed to mediate its recruitment to these structures. 66 This lipid raftmediated endocytosis has been proposed to mediate internalization of Ab peptide by primary neurons 67 and extracellular a-syn by microglial cells. 68 Whether such a mechanism could also mediate a-syn uptake by neuronal cells remains to be investigated (Figure 2b).…”