2. Academic Validation
  3. Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson's models via regulating autophagy-lysosome pathway

Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson's models via regulating autophagy-lysosome pathway

  • NPJ Parkinsons Dis. 2022 Aug 6;8(1):100. doi: 10.1038/s41531-022-00361-4.
Jie Xu  # 1,  Yun-Lin Ao  # 1,  Chunhui Huang 2,  Xiubao Song 3,  Guiliang Zhang 2,  Wei Cui 4,  Yuqiang Wang 2,  Xiao-Qi Zhang 5,  Zaijun Zhang 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Engineering Research Center for Modernization of TCM, Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
  • 2 Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
  • 3 Department of Rehabilitation, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
  • 4 Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
  • 5 Guangdong Provincial Engineering Research Center for Modernization of TCM, Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China. xqzhang74@hotmail.com.
  • 6 Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China. zaijunzhang@163.com.
  • # Contributed equally.
PMID: 35933473 DOI: 10.1038/s41531-022-00361-4
Abstract

The abnormal accumulation of α-synuclein (α-syn) is a crucial factor for the onset and pathogenesis of Parkinson's disease (PD), and the autophagy-lysosome pathway (ALP) contributes to α-syn turnover. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) regulate Autophagy by initiating the macroautophagy cascade and promoting lysosomal biogenesis via increased transcription factor EB (TFEB) activity. Hence, activation of AMPK-mTOR-TFEB axis-mediated Autophagy might promote α-syn clearance in PD. Harmol is a β-carboline alkaloid that has been extensively studied in a variety of diseases but rarely in PD models. In this study, we aimed to evaluate the effect and underlying mechanism of harmol in PD models in vitro and in vivo. We show that harmol reduces α-syn via ALP in a dose- and time-dependent manner in cell model that overexpressed human A53T mutant α-syn. We also demonstrate that harmol promotes the translocation of TFEB into the nucleus and accompanies the restoration of autophagic flux and lysosomal biogenesis. Importantly, harmol improves motor impairment and down-regulates α-syn levels in the substantia nigra and prefrontal cortex in the α-syn transgenic mice model. Further studies revealed that harmol might activate ALP through AMPK-mTOR-TFEB to promote α-syn clearance. These in vitro and in vivo improvements demonstrate that harmol activates the AMPK-mTOR-TFEB mediated ALP pathway, resulting in reduced α-syn, and suggesting the potential benefit of harmol in the treatment of PD.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z