Parallel mechanisms for direct and indirect membrane protein trafficking by synucleins

Abstract

More than 2 decades of work have yet to conclusively determine the physiological role of the synuclein proteins, even though these abundant brain constituents are participants in a broad array of cellular processes. Among proposed physiological roles is a functional interaction between the synuclein proteins and monoamine transporters contributing to transporter trafficking through direct protein-protein interactions. Recent work shows that an antagonistic effect of the synuclein proteins on the secretory functions of the endoplasmic reticulum and the Golgi apparatus appears to simultaneously influence trafficking of the dopamine transporter and other membrane proteins. Here, we highlight these new findings in view of the broader literature identifying the role of synucleins in protein trafficking and suggest emerging themes for ongoing and future work in the field of synuclein biology.

Keywords: Golgi; Parkinson’s disease; dopamine uptake; endoplasmic reticulum; mood disorders; synuclein; trafficking.

Figure 1. Evidence supports many distinct possible mechanisms that may operate simultaneously and in parallel to modulate trafficking of DAT and similarly secreted proteins in neuronal cells. The earliest steps of biosynthesis, including chaperone-mediated folding events (A) inside the ER, may be subject to interference from the Syn proteins, as several recent studies show binding with ER chaperone Grp78 and identify α-Syn inside the ER lumen.^- Syn proteins also antagonize many elements that contribute to (B) export of newly synthesized membrane proteins out of the ER and to the Golgi apparatus. The consequences of this function, which have varied widely across different model systems, range from a general slowing of the ER–Golgi transition to significant cytotoxicity.^- Syn proteins can bind tubulin and have been shown to (C) act as a bridge between DAT or NET and the microtubule cytoskeleton.^,, This tethering function serves to increase the cytosolic fraction of the transporters and reduce their distribution to the cell surface. A similar relationship has been described between α-Syn, NET, and (D) the actin cytoskeleton, which penetrates even further into the axonal synapse. The final steps required to insert DAT and related cargos into the plasma membrane at or near axonal synapses are (E) mediated by SNARE proteins.^, Assembly of SNARE proteins into functional complexes is in part dependent on appropriate levels of the Syn proteins. These findings together suggest a role for the Syn proteins in regulating the insertion of trafficked proteins into the pre-synaptic plasma membrane. Syn mRNA has been identified in the axonal transcriptome, suggesting that local translation could contribute to accumulation of the Syn proteins in the pre-synaptic area. This accumulation puts the Syn proteins in position to have a potentially large contribution to regulating (F) non-canonical secretory functions performed by axonal ER and Golgi outposts that to date remain poorly described.