ReferenceID 5660
Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models
Phytomedicine
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 dege
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- Reference Id
- 5660
- Evidence Id
- 22250
- Core Evidence Id
- 22250
- Source Reference Id
- 4546
- Herb2 Reference Id
- HBREF005343
- Subject Paper Key
- HBIN034010_34038839
- Pubmed Id
- 34038839
- Doi
- 10.1016/j.phymed.2021.153578
- Paper Title
- Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models
- Paper Abstract
- 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.
- Journal
- Phytomedicine
- Publish Year
- 2021
- Experiment Subject
- mouse; neuronal cell lines; primary cultured neurons; wild-type (wt) and mutant alpha-syn-overexpressing pc12 cells; wt alpha-syn-overexpressing n2a cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Ups Impairment; Neurodegenerative Motor Disorders; Neurodegenerative Diseases; Parkinson's Disease
- Paper Title Cn
- Paper Title En
- Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models
- Bilingual Status
- semi_complete