Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy
Authors: Mustafa Ardah
Jia-Yi Li
Meike Diepenbroek
Jia-Zhen Wu
Zhan-You Wang
Nishant N Vaikath
Caroline Haikal
Wen Li
Tiago F Outeiro
Omar M El-Agnaf
Alexander Svanbergsson
Journal: Translational neurodegeneration (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Parkinson disease; alpha-synuclein; chaperone-mediated autophagy; lysosomal-associated membrane protein; macroautophagy
Affiliations: 1Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning China., 6Key Laboratory of Maternal-Fetal Medicine of Liaoning Province and Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, China., 2Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates., 3Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, BMC A10, 221 84 Lund, Sweden., 4Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, P.O. Box 5825, Doha, Qatar., 5Institute of Heath Sciences, China Medical University, 110112 Shenyang, People's Republic of China., 7Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center G√∂ttingen, 37073 G√∂ttingen, Germany., 8Max Planck Institute for Experimental Medicine, G√∂ttingen, Germany.

Abstract:  Background: Progressive accumulation of Œ±-synuclein is a key step in the pathological development of Parkinson's disease. Impaired protein degradation and increased levels of Œ±-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 Œ±-synuclein. Dysfunction of the CMA pathway impairs Œ±-synuclein degradation and causes cytotoxicity. Results: In the present study, we investigated the effects on the CMA pathway and Œ±-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 Œ±-synuclein aggregation, after administration of DHM and Sal B, we observed significant inhibition of Œ±-synuclein accumulation and aggregation. Cells were co-transfected with a C-terminal modified Œ±-synuclein (SynT) and synphilin-1, and then treated with DHM (10 ŒºM) and Sal B (50 ŒºM) 16 hours after transfection; levels of Œ±-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 Œ±-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 Œ±-synuclein. Moreover, DHM and Sal B treatments exhibited anti-inflammatory activities, preventing astroglia- and microglia-mediated neuroinflammation in BAC-Œ±-syn-GFP transgenic mice. Conclusions: Our data indicate that DHM and Sal B are effective in modulating Œ±-synuclein accumulation and aggregate formation and augmenting activation of CMA, holding potential for the treatment of Parkinson's disease. 

Retracted: No

PubPeer comments:
 Figure 8G appears to have some images which overlap for differently treated mice. A common area on 3 images is shown. Could the authors comment? ***  ***  , 
 Hi, Thank you for pointing out the potential incorrect display of images in Fig 8G in our paper published in Translational Neurodegeneration, 2019 (doi: 10.1186 s40035-019-0159-7). This email just lets you know that we take this issue seriously. We are thoroughly investigating all the archived raw data and raw materials, such tissue sections. Due to the current coronavirus pandemic and lockdowns in some of the working premises where the raw materials were stored, it will take a bit longer time for us to conclude our investigation. We promise that we will provide a conclusive report on your critique as soon as possible. Thank you again and have a nice year of 2021. Best regards, Jiayi Li, the Corresponding author, PhD, Professor , 
 #2 Thank you for your reply. This may help with your search: ***  , 
 Also in Figure 6E is a region which unexpectedly appears twice. *** Enhanced contrast  *** Original  ,