title: α-Synuclein and protein degradation systems: a reciprocal relationship.
abstract: An increasing wealth of data indicates a close relationship between the presynaptic protein alpha-synuclein and Parkinson's disease (PD) pathogenesis. Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha-synuclein degradation in neurons remains contentious. Both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP)-mainly macroautophagy and chaperone-mediated autophagy-have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to alpha-synuclein degradation, as well as to alpha-synuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate alpha-synuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related synucleinopathies.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, Athens 11527, Greece. mxilouri@bioacademy.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Oystein Rod
authors.initials: OR
authors.lastname: Brekk
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein