Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

Abstract

Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein⁻protein and protein⁻lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

Keywords: conformational plasticity; interactome; synaptic proteins; synucleinopathies; α-synuclein.

Figure 1

Amino acid sequence and conformational variability of α-synuclein (A). The primary amino acid sequence of α-syn can be divided in three main regions: the N-terminal amphipatic domain, the central part containing the NAC sequence and the C-terminal acidic tail. Pathogenic mutations related to familiar forms of PD and the S129 phosphorylation site are also represented (B). The elevated structural plasticity of α-syn can give rise to the formation of functional dimers, tetramers and oligomers or high molecular weight aggregation-prone oligomers, protofibrils and fibrils.

Figure 2

Role of α-syn in axonal trafficking and synaptic terminals. The image is representative of α-syn interactome in axons (A) and synapses (B). (A) Alpha-synuclein interacts with different motor proteins mediating axonal transport, such as kinesins and dyneins, as well as with microtubules, where it contributes to the polymerization of the single tubulin molecules. (B) At the synapse α-syn plays multiple important roles in SVs trafficking and refilling and in neurotransmitter release and reuptake. Alpha-synuclein aggregation perturbs the distribution and function of its synaptic partners.

Figure 3

Overview of the α-syn interactome at SV. Alpha-synuclein interacts with multiple SV proteins as well as with SV membranes. By orchestrating its SV partners, α-syn contributes to neurotransmitter filling, SV tethering, docking and fusion. Please note that syn III is the abbreviation for synapsin III.