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.

How strong is the evidence that Parkinson's disease is a prion disorder?

“…In cell cultures, α-synuclein is released via exocytosis and the process is enhanced by cellular stress such as inhibition of lysosomes (66–70). A minor portion (frequently estimated at around 5%) of the extracellular α-synuclein is associated with exosomes and it can be present in oligomeric forms, both on the inside and surface of the microvesicles (68,69,71,72). It is unclear whether all of the α-synuclein found in the exosomal fraction is secreted with the exosomes or whether they associate with each other outside the cell.…”

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

“…At the subcellular level, it has been observed that, in neurons, α -synuclein can be found in the three endosomal compartments and translocate across them (early, late, and recycling endosomes) [32]. This pathway could be involved in the process of protein release [32].…”

“…This pathway could be involved in the process of protein release [32]. Moreover, treatments that could disturb the homeostasis of the endosomal system alter α -synuclein spreading [63, 157].…”

“…These evidences pose into question both the trans-synaptic spreading hypothesis and the prion-like behavior of α -synuclein. Nonetheless, cell-to-cell transmission of α -synuclein can occur with Ca 2+ -dependent exosome-mediated release [32] or nonclassical exocytosis [33] as the most plausible candidate mechanisms for α -synuclein ejection. Finally, what could be the transmissible form of the protein that can mediate toxicity and/or function as seed for “misfolding” propagation in recipient cells between monomeric, oligomeric, and fibrillary α -synuclein still needs to be clarified.…”

Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease

“…This is critical to understand disease propagation through synaptically connected regions along the whole CNS. In this way, VPS mutations may be a pivot to understand cell-to-cell transmission of protein cargoes through exosomes (Danzer et al, 2012; Poehler et al, 2014; Tsunemi et al, 2014; Emmanouilidou and Vekrellis, 2016; Lööv et al, 2016; Figure 1). Thus, an in depth analysis of VPS alterations is expected to disclose the anatomical basis of disease progression as recently described (Hawkes et al, 2010; Del Tredici and Braak, 2013; Holmqvist et al, 2014; Garcia-Esparcia et al, 2015; Lamberts et al, 2015).…”