Exogenous  -Synuclein Decreases Raft Partitioning of Cav2.2 Channels Inducing Dopamine Release

Abstract

␣-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. ␣-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of ␣-synuclein-derived pathology. ␣-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that ␣-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Ca v 2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of ␣-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that ␣-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Ca v 2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which ␣-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of ␣-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization

“…Despite our lack of functional understanding of carboxyl-terminal modifications, these observations are consistent with evidence that long range carboxyl-terminal effects impact helix formation and binding efficiency of the aminoterminal amphipathic domain (67,68). In addition, extracellular ␣-syn binding to biological membranes may also involve coordination with lipids and additional protein components in lipid raft domains via the carboxyl terminus (24,69,70). For example, there is evidence that the portion of the carboxylterminal domain containing the serine 129 residue of synaptic vesicle-bound ␣-syn can interact with synaptobrevin (6).…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…Interestingly, oxidative stress, a process implicated in neuronal toxicity may also result in generation of α-synuclein oligomers (Norris et al, 2003). Alfa-synuclein is a protein that is intimately involved in maintaining the supply of synaptic vesicles in presynaptic terminals and may also help regulate the release of DA (Ronzitti et al, 2014). Alfa-synuclein is localized in the cytosol as well as in the inner membrane of neuronal mitochondria where it may exert an inhibitory effect on complex I activity of mitochondrial respiratory chain, predisposing some neurons to degeneration (Liu et al, 2009;Lam et al, 2011;Gaugler et al, 2012).…”

A Modular Assembly of Spinal Cord–Like Tissue Allows Targeted Tissue Repair in the Transected Spinal Cord

“…Transient increase of calcium surges was observed following an excitatory glutamate (Figure 3e1–e3) or high [K + ] stimulation (Figure 3f1–f3). The spontaneous calcium surges could be blocked by tetrodotoxin (TTX, Figure 3g1–g3), suggesting that TTX‐sensitive voltage‐gated sodium channels, which contribute to the forming of action potentials in mature neurons,16 might exist in the neurons in the SCLT as well. On the other hand, neurons in the singly cultured GMLT did not present vesicle releasing capability following high [K + ] stimulation nor Ca 2+ oscillations activity, suggesting that they may not resemble mature neuronal properties (Figure S2, Supporting Information).…”