The regulation of synaptic function by alpha-synuclein

Abstract

The cytosolic protein alpha-synuclein is enriched at the pre-synaptic terminals of almost all types of neurons in the central nervous system. alpha-Synuclein overexpression and the expression of three different mutants have been shown to sustain the pathogenesis of selected forms of Parkinson's disease. The localization of the protein and the defects found in knocked out or transgenic animals suggest a role of alpha-synuclein in the regulation of synaptic efficiency. However, the precise function of the protein and the molecular mechanisms of its action are still unclear. At synapses the synaptic vesicle release cycle is a finely tuned process composed of sequential steps that require the interconnected participation of several proteins and cytoskeletal elements. Actin microfilaments are required for the regulation of synaptic vesicle mobilization between different functional pools, for their organization at the active zone and influence the exocytotic process. We recently identified actin as a possible target of alpha-synuclein function. Through its binding to actin and the regulation of actin dynamics, alpha-synuclein could participate in the tuning of the vesicle release process, thereby modulating synaptic function and plasticity.

Keywords: actin cytoskeleton; exocytosis; synaptic plasticity; synaptic vesicles; α-synuclein.

Figure 1

Actin and the synaptic vesicle cycle. Synaptic vesicles are tethered in the reserve pool (RP) by a network of actin filaments. Small GTPases, such as RhoA and Rac1, control the state of actin polymerization by governing pathways that involve phosphorylation/dephosphorylation of different actin-binding proteins. The WASP protein and the Arp2/3 complex promote the actin filament nucleation process necessary to build actin tracks for vesicles trafficking. Vesicles are transported to the active zone along actin filaments by myosin V, which also contributes to vesicles docking via its binding to syntaxin1. Primed vesicles are part of the ready releasable pool (RR P). Ca²⁺ influx and the assembly of the SNARE ternary complex formed by the α-helices of VAMP2, SNAP25 and syntaxin1, trigger vesicle exocytosis at the active zones plasma membrane. Therefore, actin regulates priming and fusion, directly affecting neurotransmitter release. In addition it constitutes the tracks that guide recycling vesicles back to the RP.

Figure 2

Hypothetical model of α-synuclein action on actin dynamics. At synaptic terminals α-synuclein is associated with synaptic vesicles. At rest, when [Ca²⁺]_c is around 100 nM, α-synuclein binds preferentially actin monomers, sequestering them and slowing down the polymerization of microfilaments. When [Ca²⁺]_c rises upon cell stimulation, α-synuclein affinity for actin monomers decreases and binding to filaments prevails, shifting the balance toward polymerization. This series of events is expected to facilitate the maintenance of vesicles in the RP and, at the same time, to favour the formation of the tracks and the clustering of molecules necessary for vesicles docking and fusion to take place.