Exocytosis and Spreading of Normal and Aberrant α-Synuclein

Abstract

It is now established that α-synuclein can be physiologically secreted to the extracellular space. In this sense, mechanisms that govern the secretion of the protein may be of importance in the initiation and progress of synucleinopathies. It is possible that increased secretion may aid the formation of toxic seeds extracellularly. Alternatively, reduced presence of extracellular α-synuclein due to impaired secretion may increase the intracellular load and trigger intracellular seeding. Once outside, α-synuclein can exert various paracrine actions on neighboring cells again by mechanisms that have not been fully elucidated. It has been demonstrated that, when applied extracellularly, α-synuclein species can induce multiple neurotoxic and inflammatory responses, and aid the transmission of pathology between neurons. Still, the exact mechanism(s) by which secreted α-synuclein affects the homeostasis of other neurons is still not well understood. A portion of α-synuclein has been shown to be associated with the surface and lumen of exosomes which can transfer it to the surrounding cells, and potentially trigger seeding. Interestingly, increased exosome release has been linked to pathological situations of lysosomal dysfunction as observed in Parkinson's disease (PD). However, the possibility that the observed α-synuclein pathology spread is attributable to the passive diffusion of the initial injected α-synuclein strains cannot be excluded. Importantly, most of the studies that have so far addressed the role of extracellular α-synuclein have not employed naturally secreted forms of the protein. It is plausible that deregulation in the normal processing of secreted α-synuclein may aid the formation of "toxic" species and as such it may also be a causative risk factor for PD. In this capacity, elucidation of the underlying mechanisms that regulate the protein-levels of extracellular α-synuclein becomes essential. Such mechanisms could involve its proteolytic clearance from the extracellular milieu.

Keywords: aggregates; exocytosis; exosomes; propagation; α-synuclein.

Figure 1

Proposed pathways for α‐synuclein exocytosis. α‐synuclein (red line) is associated with synaptic vesicles promoting the SNARE complex assembly and facilitating neurotransmitter release 1. The synaptic vesicle‐free can enter the early endosomal compartment via Golgi or clathrin‐mediated endocytosis 2. Endosome‐residing α‐synuclein can be then secreted by two separate pathways. It can be incorporated in MVBs 12 with the assistance of VSP4 and SUMO proteins and be externalized as exosome cargo on fusion of the MVB with the plasma membrane. Alternatively, it can be sorted into recycling endosomes 5 and be released possibly via secretory granules in a Rab11a‐dependent fashion. In all cases, α‐synuclein release is regulated by intracellular calcium concentration.

Figure 2

Possible mechanisms for uptake and propagation of α‐synuclein. Exogenous α‐synuclein (red line) can enter neuronal cells via various, yet unidentified, pathways such as translocation through a membrane pore or protein complex 2, exosome fusion with the plasma membrane 12 or endocytosis 5. The internalized protein can then act as a template to assist the production of higher order α‐synuclein species during a process where the endogenous α‐synuclein (red cube) is also incorporated. Alternatively, exogenous α‐synuclein species can interact with a receptor protein in the plasma membrane 1 signaling the seeding of endogenous α‐synuclein and generating aggregated α‐synuclein material. In all cases, aggregated α‐synuclein can be externalized and affect neighboring neurons.