Distinct Roles In Vivo for the Ubiquitin-Proteasome System and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein

Increased intracellular levels of alpha-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how alpha-synuclein is degraded by neurons in vivo. To address this, our study uses alpha-synuclein transgenic mice, expressing human alpha-synuclein or alpha-synuclein-eGFP under the (h) PDGF-beta promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for alpha-synuclein under normal conditions in vivo while with increased alpha-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS in alpha-synuclein transgenic mice and age dependence to the role of the UPS in alpha-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and alpha-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.