BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders, and is characterized by the presence of Lewy bodies containing misfolded alpha-synuclein (alpha-syn) and by selective degeneration of midbrain dopamine neurons. Studies have shown that upregulation of ubiquitin-proteasome system (UPS) activity promotes the clearance of aggregation-prone proteins such as alpha-syn and Tau, so as to alleviate the neuropathology of neurodegenerative diseases. PURPOSE: To identify and investigate lycorine as a UPS enhancer able to decrease alpha-syn in transgenic PD models. METHODS: Dot blot was used to screen alpha-syn-lowering compounds in an inducible alpha-syn overexpression cell model. Inducible wild-type (WT) and mutant alpha-syn-overexpressing PC12 cells, WT alpha-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on alpha-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on alpha-syn degradation in vivo. mCherry-GFP-LC3 reporter was used to detect autophagy-dependent degradation. Ub-R-GFP and Ub-G76V-GFP reporters were used to detect UPS-dependent degradation. Proteasome activity was detected by fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC (Suc-LLVY-AMC). RESULTS: Lycorine significantly promoted clearance of over-expressed WT and mutant alpha-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days' intraperitoneal administration of lycorine effectively promoted the degradation of alpha-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated alpha-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote proteasome activity. CONCLUSION: Lycorine is a novel alpha-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower alpha-syn implies that lycorine has the potential to be developed as a pharmaceutical for the treatment of neurodegenerative diseases, such as PD, associated with UPS impairment and protein aggregations. CI - Copyright (c) 2021. Published by Elsevier GmbH.