Protein Partners of α-Synuclein in Health and Disease

Abstract

α-synuclein is normally situated in the nerve terminal but it accumulates and aggregates in axons and cell bodies in synucleinopathies such as Parkinson's disease. The conformational changes occurring during α-synucleins aggregation process affects its interactions with other proteins and its subcellular localization. This review focuses on interaction partners of α-synuclein within different compartments of the cell with a focus on those preferentially binding aggregated α-synuclein. The aggregation state of α-synuclein also affects its catabolism and we hypothesize impaired macroautophagy is involved neuronal excretion of α-synuclein species responsible for the prion-like spreading of α-synuclein pathology.

Keywords: Lewy Body; Parkinson's disease; dementia; neurodegeneration; protein interaction; proteomics; α-synuclein.

Figure 1

Hypothetical involvement of impaired macroautophagy in neuronal excretion of prion‐like oligomeric α‐synuclein species. Normal conditions: Native or monomeric α‐synuclein (M) is produced in the nerve cell body and transported by anterograde axonal transport to the nerve terminal, where it is present in a high concentration. In nerve terminals, some native α‐synuclein will be degraded by the ubiquitin‐proteasome and some will be transported back to the cell body by retrograde transport. In the cell body, where lysosomes are present, native α‐synuclein can be catabolized by the chaperone mediated autophagic (CMA) system and the ubiquitin‐proteasome system. The high concentration of α‐synuclein in nerve terminals favors some degree of aggregation of native α‐synuclein into low amounts of oligomers (O), which will be recognized by the macroautophagic system and packaged into autophagosomes. The autophagosomes will be transported by retrograde axonal transport to the cell body, where they complete the macroautophagic process by fusing with lysosomes. Synucleinopathies: Build‐up of oligomers (O) in nerve terminals inhibits the ubiquitin‐proteasome system causing increase of native α‐synuclein (M) and further generation of oligomers. The macroautophagy system recognizes the oligomers leading to increased levels of oligomer‐containing autophagosomes that are transported to the cell body by retrograde axonal transport. The increased load of autophagomes in terminals initiates the process of exophagy, where autophagosomes fuse with the plasma membrane releasing their inner oligomer‐containing vesicle to the extracellular space. Extracellularly these vesicles may be taken up by neighboring cells, or the membrane may lyse leaving the oligomers as free particles. In the cell body, increased levels of oligomers inhibit both the ubiquitin‐proteasome system and the chaperone mediated autophagy system leaving the macroautophagic system to dispose of the misfolded α‐synuclein species. However, aberrant α‐synuclein inhibits the fusion of autophagosomes with lysosomes increasing the flow through the exophagic pathway. Moreover, the cell initiates formation of Lewy bodies to dispose of the increased levels of aggregated α‐synuclein. Conclusively, the increased formation of autophagosomes, which contain oligomeric α‐synuclein species selected by the cellular quality‐control system, combined with a decreased ability to fuse autophagosomes with lysosomes favor exophagy and spreading of aggregated α‐synuclein species that is able to trigger prion‐like spreading upon uptake by neighboring neurons.