Table 6.
Summary table on α-synuclein (α-syn) lipid interactions and synaptic dysfunctions in different models. The table provides the main information on α-syn wild type and PD-associated modifications (first column) and their effect on membrane lipids interaction (second column) that has been extensively described in Section 2. The mains functional effects of α-syn on the different steps of exocytosis are also described, highlighting the role of α-syn on the regulation of docking vesicles (third column, explained in the Section 3.1), fusion pore (fourth column, described in Section 3.2), exocytosis (fifth column, Section 3.3 and Section 3.4), and vesicle recycling (sixth column, Section 3.5).
| Type of α-Syn Modifications | Lipid Effect | Vesicle Trafficking | |||
|---|---|---|---|---|---|
| Docking | Fusion Pore | Exocytosis | Recycling | ||
| WT 140 | Increased α-helical multimers formation. | Increased cluster of VAMP2- vesicles and SNARE complex assembly. | |||
| A30P 140 | Decreased membrane binding. Decreased membrane curvature. Abolition of interaction with lipid-rafts. |
Accumulation of docked vesicles at the plasma membrane. Decreased priming of neurosecretory vesicles. |
Perturbation of fusion pore formation. | Decreased catecholamine release. No change in synaptic exocytosis. |
|
| A53T 140 | Increased multimerisation long chain PUFA-mediated. Decreased multimerisation mediated by saturated fatty acids. No change in lipid binding. |
Clustering of VAMP2 SV at the active zone. | Perturbation of fusion pore formation. | Perturbation of SV recycling. | |
| E46K 140 | Clustering of VAMP2 SV at the active zone. | ||||
| K O * | Decreased reserve pool. | Increased concentration of VMAT2 molecules per vesicle. | Increased dopamine release. | ||
| Overexpression | Decreased membrane curvature induction. Increased oleic acid and unsaturated fatty acid. |
Decreased reserve vesicles. Decreased vesicle density. |
Prevention the fusion pore closure. | Rescue the SNARE-complex assembly deficit in CSPα-KO mice. Decreased level of synapsins and complexins. |
Increased cytosolic dopamine levels due to inhibition of VMAT2 activity. |
| Overexpression in CSPα-KO mice | Rescues the SNARE-complex assembly deficit. | Prevents neurodegeneration. | |||
| WT 112 | Increased phospholipid binding Increased tendency to oligomerisation. |
Perturbation SV recycling. | |||
| Soluble aggregates | Increased aggregates by PUFA. | ||||
| Pathological aggregates | Increased aggregation by cholesterol, lipids with short saturated acyl chain, GM1, and GM3. | Perturbation of vesicles docking at the presynaptic terminal. | Increased VAMP2 binding affinity. | Alteration in neurotransmission. | |
Legend. α-syn = α-synuclein, CSPα = cysteine-string protein-α, GM = gangliosides, KO = knockout, PUFA = polyunsaturated fatty acids, SNARE = soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor, SV = synaptic vesicles, VAMP2 = vesicle associated membrane protein 2, VMAT2 = vesicular monoamine transporter 2, WT = wild type. * see Table 4. The effect on exocytosis depends on the knockout model.