TY - JOUR
T1 - Inhibition of alpha-synuclein seeded fibril formation and toxicity by herbal medicinal extracts
AU - Ardah, Mustafa T.
AU - Ghanem, Simona S.
AU - Abdulla, Sara A.
AU - Lv, Guohua
AU - Emara, Mohamed M.
AU - Paleologou, Katerina E.
AU - Vaikath, Nishant N.
AU - Lu, Jia Hong
AU - Li, Min
AU - Vekrellis, Konstantinos
AU - Eliezer, David
AU - El-Agnaf, Omar M. A.
N1 - Funding information:
The work conducted by Dr. El-Agnaf laboratory was supported by Qatar Biomedical Research Institute under the Start-up Fund SF 2017–007. Funding for this work was provided in part by NIH/NIA grant R37AG019391 to D.E. This study was made possible by NPRP grant 4–1371–1-223 from the Qatar National Research Fund (a member of Qatar Foundation).
Publisher copyright:
© The Author(s). 2020
PY - 2020/3/6
Y1 - 2020/3/6
N2 - BackgroundRecent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies. MethodsUsing biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process. ResultsSalvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion. ConclusionsEleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.
AB - BackgroundRecent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies. MethodsUsing biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process. ResultsSalvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion. ConclusionsEleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.
KW - Amyloid fibrils
KW - Dihydromyricetin
KW - Parkinson’s disease
KW - Salvianolic acid B
KW - Seeded fibril formation
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=85090320127&partnerID=8YFLogxK
U2 - 10.1186/s12906-020-2849-1
DO - 10.1186/s12906-020-2849-1
M3 - Journal article
C2 - 32143619
AN - SCOPUS:85090320127
SN - 2662-7671
VL - 20
JO - BMC Complementary Medicine and Therapies
JF - BMC Complementary Medicine and Therapies
M1 - 73
ER -