Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models

  • Phytomedicine. 2021 Jul:87:153578. doi: 10.1016/j.phymed.2021.153578.
Qi Zhu  1 ,  Xu-Xu Zhuang  1 ,  Jia-Yue Chen  1 ,  Ning-Ning Yuan  1 ,  Yan Chen  1 ,  Cui-Zan Cai  1 ,  Jie-Qiong Tan  2 ,  Huan-Xing Su  1 ,  Jia-Hong Lu  3
Affiliations
  • 1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
  • 2. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
  • 3. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China. Electronic address: [email protected].
PMID: 34038839 DOI: 10.1016/j.phymed.2021.153578
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 α-synuclein (α-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 α-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 α-syn in transgenic PD models.

Methods: Dot blot was used to screen α-syn-lowering compounds in an inducible α-syn overexpression cell model. Inducible wild-type (WT) and mutant α-syn-overexpressing PC12 cells, WT α-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on α-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 α-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days' intraperitoneal administration of lycorine effectively promoted the degradation of α-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated α-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote Proteasome activity.

Conclusion: Lycorine is a novel α-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower α-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.

Keywords
Lycorine; Parkinson's disease; Ubiquitin-proteasome system; cAMP/PKA pathway; α-synuclein.
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