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.
(Less)
- author
- 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. (More)
- 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
; El-Agnaf, Omar M
and Li, Jia-Yi
LU
(Less)
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Translational Neurodegeneration
- volume
- 8
- article number
- 18
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:31223479
- scopus:85067310536
- ISSN
- 2047-9158
- DOI
- 10.1186/s40035-019-0159-7
- language
- English
- LU publication?
- yes
- id
- e1b60156-f7a9-462c-a6c9-eff225cd97c0
- date added to LUP
- 2019-06-23 14:12:36
- date last changed
- 2024-04-02 09:33:30
@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>}},
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 (BMC)}},
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}},
doi = {{10.1186/s40035-019-0159-7}},
volume = {{8}},
year = {{2019}},
}