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

Jia Zhen Wu, Mustafa Ardah, Caroline Haikal, Alexander Svanbergsson, Meike Diepenbroek, Nishant Vaikath, Wen Li, Zhan You Wang, Tiago F. Outeiro, Omar Ali El-Agnaf, Jia Yi Li

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Article number18
JournalTranslational Neurodegeneration
Volume8
Issue number1
DOIs
Publication statusPublished - 15 Jun 2019

Fingerprint

Synucleins
alpha-Synuclein
Autophagy
Parkinson Disease
salvianolic acid B
dihydromyricetin
Microglia
Medicinal Plants
Astrocytes
Transgenic Mice

Keywords

  • alpha-synuclein
  • chaperone-mediated autophagy
  • lysosomal-associated membrane protein
  • macroautophagy
  • Parkinson disease
  • protein aggregation

ASJC Scopus subject areas

  • Clinical Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy. / Wu, Jia Zhen; Ardah, Mustafa; Haikal, Caroline; Svanbergsson, Alexander; Diepenbroek, Meike; Vaikath, Nishant; Li, Wen; Wang, Zhan You; Outeiro, Tiago F.; Ali El-Agnaf, Omar; Li, Jia Yi.

In: Translational Neurodegeneration, Vol. 8, No. 1, 18, 15.06.2019.

Research output: Contribution to journalArticle

Wu, Jia Zhen ; Ardah, Mustafa ; Haikal, Caroline ; Svanbergsson, Alexander ; Diepenbroek, Meike ; Vaikath, Nishant ; Li, Wen ; Wang, Zhan You ; Outeiro, Tiago F. ; Ali El-Agnaf, Omar ; Li, Jia Yi. / Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy. In: Translational Neurodegeneration. 2019 ; Vol. 8, No. 1.
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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 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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AU - Wu, Jia Zhen

AU - Ardah, Mustafa

AU - Haikal, Caroline

AU - Svanbergsson, Alexander

AU - Diepenbroek, Meike

AU - Vaikath, Nishant

AU - Li, Wen

AU - Wang, Zhan You

AU - Outeiro, Tiago F.

AU - Ali El-Agnaf, Omar

AU - Li, Jia Yi

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N2 - 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.

AB - 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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KW - chaperone-mediated autophagy

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