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.

The good and bad of therapeutic strategies that directly target α‐synuclein

“…Under physiological conditions, α‐syn is enriched at presynaptic boutons . However, its expression is not homogeneous within the terminals of diverse neuronal populations .…”

“…Although the physiological functions of α‐syn still need to be fully elucidated, a crucial interplay has been observed between α‐syn and synaptic proteins including synapsins, the soluble NSF attachment protein receptors (SNARE) protein VAMP‐2, synphilin‐1, and synaptic vesicle glycoprotein 2C (SV2C) . However, the function and expression of synaptic proteins such as synapsins can severely diverge within different neuronal subtypes, suggesting that α‐syn may also exhibit a different action profile in relation to the specific cellular entourage.…”

“…α‐Syn can also influence the neuronal protein trafficking by interacting with cytoskeletal components. Moreover, it can act as a molecular chaperone and promote lipid membrane curvature, thus facilitating the generation of small vesicles such as synaptic vesicles…”

“…Since α‐syn is intrinsically disordered and does not own a defined tertiary structure in solution, while displaying different conformations depending on the surrounding environment (partially α‐helical and oligomeric species), it is also difficult to predict which are most relevant functional forms of the protein . This notwithstanding, both oligomers and fibrils have been found to induce neuronal cell death, and can mediate the dissemination of α‐syn pathology, although fibrils are considered the most prone to trigger the prion‐like spreading …”

“…Since α-syn is intrinsically disordered and does not own a defined tertiary structure in solution, while displaying different conformations depending on the surrounding environment (partially α-helical and oligomeric species), it is also difficult to predict which are most relevant functional forms of the protein. 4,5 This notwithstanding, both oligomers and fibrils have been found to induce neuronal cell death, [6][7][8] and can mediate the dissemination of α-syn pathology, although fibrils are considered the most prone to trigger the prion-like spreading. 6,[8][9][10][11] This evidence supports that as α-syn deposition plays a central role in the onset of several neurodegenerative disorders, reducing α-syn levels, oligomer formation, fibrillation, or cell-to-cell transmission, may all represent useful strategies to contrast/slow down the synucleinopathies, which still nowadays can only be managed by symptomatic therapies.…”