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Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy

Wu, Jia-Zhen; Ardah, Mustafa; Haikal, Caroline LU ; Svanbergsson, Alexander LU ; Diepenbroek, Meike LU ; Vaikath, Nishant N LU ; Li, Wen LU ; Wang, Zhan-You; Outeiro, Tiago F and El-Agnaf, Omar M, et al. (2019) In Translational Neurodegeneration 8.
Abstract

Background: Progressive accumulation of α-synuclein is a key step in the pathological development of Parkinson's disease. Impaired protein degradation and increased levels of α-synuclein may trigger a pathological aggregation in vitro and in vivo. The chaperone-mediated autophagy (CMA) pathway is involved in the intracellular degradation processes of α-synuclein. Dysfunction of the CMA pathway impairs α-synuclein degradation and causes cytotoxicity.

Results: In the present study, we investigated the effects on the CMA pathway and α-synuclein aggregation using bioactive ingredients (Dihydromyricetin (DHM) and Salvianolic acid B (Sal B)) extracted from natural medicinal plants. In both cell-free and cellular models of α-synuclein... (More)

Background: Progressive accumulation of α-synuclein is a key step in the pathological development of Parkinson's disease. Impaired protein degradation and increased levels of α-synuclein may trigger a pathological aggregation in vitro and in vivo. The chaperone-mediated autophagy (CMA) pathway is involved in the intracellular degradation processes of α-synuclein. Dysfunction of the CMA pathway impairs α-synuclein degradation and causes cytotoxicity.

Results: In the present study, we investigated the effects on the CMA pathway and α-synuclein aggregation using bioactive ingredients (Dihydromyricetin (DHM) and Salvianolic acid B (Sal B)) extracted from natural medicinal plants. In both cell-free and cellular models of α-synuclein aggregation, after administration of DHM and Sal B, we observed significant inhibition of α-synuclein accumulation and aggregation. Cells were co-transfected with a C-terminal modified α-synuclein (SynT) and synphilin-1, and then treated with DHM (10 μM) and Sal B (50 μM) 16 hours after transfection; levels of α-synuclein aggregation decreased significantly (68% for DHM and 75% for Sal B). Concomitantly, we detected increased levels of LAMP-1 (a marker of lysosomal homeostasis) and LAMP-2A (a key marker of CMA). Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A with α-synuclein inclusions after treatment with DHM and Sal B. We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo, along with decreased levels of α-synuclein. Moreover, DHM and Sal B treatments exhibited anti-inflammatory activities, preventing astroglia- and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice.

Conclusions: Our data indicate that DHM and Sal B are effective in modulating α-synuclein accumulation and aggregate formation and augmenting activation of CMA, holding potential for the treatment of Parkinson's disease.

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Translational Neurodegeneration
volume
8
publisher
BioMed Central
external identifiers
  • scopus:85067310536
ISSN
2047-9158
DOI
10.1186/s40035-019-0159-7
language
English
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yes
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e1b60156-f7a9-462c-a6c9-eff225cd97c0
date added to LUP
2019-06-23 14:12:36
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2019-07-30 05:04:35
@article{e1b60156-f7a9-462c-a6c9-eff225cd97c0,
  abstract     = {<p>Background: Progressive accumulation of α-synuclein is a key step in the pathological development of Parkinson's disease. Impaired protein degradation and increased levels of α-synuclein may trigger a pathological aggregation in vitro and in vivo. The chaperone-mediated autophagy (CMA) pathway is involved in the intracellular degradation processes of α-synuclein. Dysfunction of the CMA pathway impairs α-synuclein degradation and causes cytotoxicity.</p><p>Results: In the present study, we investigated the effects on the CMA pathway and α-synuclein aggregation using bioactive ingredients (Dihydromyricetin (DHM) and Salvianolic acid B (Sal B)) extracted from natural medicinal plants. In both cell-free and cellular models of α-synuclein aggregation, after administration of DHM and Sal B, we observed significant inhibition of α-synuclein accumulation and aggregation. Cells were co-transfected with a C-terminal modified α-synuclein (SynT) and synphilin-1, and then treated with DHM (10 μM) and Sal B (50 μM) 16 hours after transfection; levels of α-synuclein aggregation decreased significantly (68% for DHM and 75% for Sal B). Concomitantly, we detected increased levels of LAMP-1 (a marker of lysosomal homeostasis) and LAMP-2A (a key marker of CMA). Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A with α-synuclein inclusions after treatment with DHM and Sal B. We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo, along with decreased levels of α-synuclein. Moreover, DHM and Sal B treatments exhibited anti-inflammatory activities, preventing astroglia- and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice.</p><p>Conclusions: Our data indicate that DHM and Sal B are effective in modulating α-synuclein accumulation and aggregate formation and augmenting activation of CMA, holding potential for the treatment of Parkinson's disease.</p>},
  articleno    = {18},
  author       = {Wu, Jia-Zhen and Ardah, Mustafa and Haikal, Caroline and Svanbergsson, Alexander and Diepenbroek, Meike and Vaikath, Nishant N and Li, Wen and Wang, Zhan-You and Outeiro, Tiago F and El-Agnaf, Omar M and Li, Jia-Yi},
  issn         = {2047-9158},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {Translational Neurodegeneration},
  title        = {Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy},
  url          = {http://dx.doi.org/10.1186/s40035-019-0159-7},
  volume       = {8},
  year         = {2019},
}