Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications

Abstract

Since its discovery, the study of the biological role of α-synuclein and its pathological implications has been the subject of increasing interest. The propensity to adopt different conformational states governing its aggregation and fibrillation makes this small 14-kDa cytosolic protein one of the main etiologic factors associated with degenerative disorders known as synucleinopathies. The structure, function, and toxicity of α-synuclein and the possibility of different therapeutic approaches to target the protein have been extensively investigated and reviewed. One intriguing characteristic of α-synuclein is the different ways in which it interacts with lipids. Though in-depth studies have been carried out in this field, the information they have produced is puzzling and the precise role of lipids in α-synuclein biology and pathology and vice versa is still largely unknown. Here we provide an overview and discussion of the main findings relating to α-synuclein/lipid interaction and its involvement in the modulation of lipid metabolism and signaling.

Keywords: lipid metabolism; lipid signal transduction; lipids; membrane lipids; α–synuclein.

FIGURE 1

α-Synuclein/lipid interactions: from the plasma membrane to intracellular compartments and extracellular vesicles. Soluble α-synuclein exists as a random coil three-dimensional structure. Membrane targeting with acidic PLs (PS and PI) triggers α-helical folding at the N-terminal domain. Protein pathological conformation is predominantly represented by β-sheet oligomers and amyloid fibrils. α-Synuclein pathological aggregation is dependent on the protein/lipid ratio. Spreading of α-synuclein, largely attributed to exosomes, is also regulated by its interaction with the PLs of the extracellular vesicles. Free fatty acids, mainly DHA, are able to induce α-synuclein oligomerization. After the interaction with lipid peroxidation products, α-synuclein is prone to the formation of toxic stable oligomers. α-Synuclein also regulates Chol efflux via ABCA1 transporter. DHA, docosahexaenoic acid; PA: phosphatidic acid; PI, phosphatidylinositol; PS, phosphatidylserine.

FIGURE 2

Crosstalk between α-synuclein and lipid metabolism. Knock-down and overexpression of α-synuclein have demonstrated the involvement of the protein in lipid metabolism. In α-synuclein knock-out mice, AA and DHA, the main polyunsaturated fatty acids in the brain, are oppositely metabolized: whereas AA intake is diminished, DHA turnover and acylation in PI and PS are increased. α-Synuclein overexpression triggers an increase in TAG content and LD accumulation by stimulation of acyl-CoA synthetase activity and probably the modulation of HMG-CoA reductase. AA, arachidonic acid; DHA, docosahexaenoic acid; HMG-CoA, 3-Hydroxy-3-methyl glutaryl coenzyme A; LD, lipid droplet; PI, phosphatidylinositol; PS, phosphatidylserine; TAG, triacylglycerol.

FIGURE 3

α-Synuclein and the modulation of lipid signaling. α-Synuclein is able to intervene lipid signaling by the modulation of phospholipase activities. The α-synuclein -induced impairment of cPLA2 and iPLA2 signaling triggers an imbalance in the AA/DHA ratio that finally could affect the balance of inflammation and resolution processes. Calcium signaling and ERK 1/2 activation are modulated by α-synuclein through PLC pathway impairment. α-Synuclein intervention in PLD signaling impacts on diverse cellular functions as vesicular trafficking, membrane curvature, and membrane protein targeting, lysosomal activity and PA-dependent signaling. AA, arachidonic acid; DHA, docosahexaenoic acid; PA, phosphatidic acid; cPLA2, calcium-sensitive cytosolic phospholipase A2; iPLA2, calcium-independent phospholipase A2; PLC, phospholipase C; PLD, phospholipase D.