Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

The accumulation and aggregation of α-synuclein (α-syn) is the main pathologic event in Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-Syn-seeded fibril formation and its induced toxicity occupy a major role in PD pathogenesis. Thus, assessing compounds that inhibit this seeding process is considered a key towards the therapeutics of synucleinopathies. Using biophysical and biochemical techniques and seeding-dependent cell viability assays, we screened a total of nine natural compounds of alkaloid origin extracted from Chinese medicinal herbs. Of these compounds, synephrine, trigonelline, cytisine, harmine, koumine, peimisine, and hupehenine exhibited in vitro inhibition of α-syn-seeded fibril formation. Furthermore, using cell viability assays, six of these compounds inhibited α-syn-seeding-dependent toxicity. These six potent inhibitors of amyloid fibril formation and toxicity caused by the seeding process represent a promising therapeutic strategy for the treatment of PD and other synucleinopathies.

Download Full-text

Faculty Opinions recommendation of Amyloid fibril formation of alpha-synuclein is accelerated by preformed amyloid seeds of other proteins: implications for the mechanism of transmissible conformational diseases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028776.342335 ◽

2005 ◽

Author(s):

George Perry

Keyword(s):

Amyloid Fibril ◽

Alpha Synuclein ◽

Fibril Formation ◽

Conformational Diseases ◽

Amyloid Fibril Formation

Download Full-text

Techniques to study amyloid fibril formation in vitro

Methods ◽

10.1016/j.ymeth.2004.03.012 ◽

2004 ◽

Vol 34 (1) ◽

pp. 151-160 ◽

Cited By ~ 611

Author(s):

M NILSSON

Keyword(s):

Amyloid Fibril ◽

Fibril Formation ◽

Amyloid Fibril Formation

Download Full-text

Ion Mobility Mass Spectrometry Studies of the Inhibition of Alpha Synuclein Amyloid Fibril Formation by ( - )-Epigallocatechin-3-Gallate

Australian Journal of Chemistry ◽

10.1071/ch10334 ◽

2011 ◽

Vol 64 (1) ◽

pp. 36 ◽

Cited By ~ 11

Author(s):

Yanqin Liu ◽

Lam H. Ho ◽

John. A. Carver ◽

Tara L. Pukala

Keyword(s):

Mass Spectrometry ◽

Conformational Change ◽

Ion Mobility ◽

Amyloid Fibril ◽

Heterogeneous Systems ◽

Alpha Synuclein ◽

Fibril Formation ◽

Ion Mobility Mass Spectrometry ◽

Compact Structure ◽

Amyloid Fibril Formation

Ion mobility-mass spectrometry (IM-MS) is emerging as an important biophysical technique for the structural analysis of proteins and their assemblies, in particular for structurally heterogeneous systems such as those on the protein misfolding and aggregation pathway. Using IM-MS we have monitored amyloid fibril formation of A53T α-synuclein, a mutant synuclein protein associated with Parkinson’s disease, and identified that a conformational change towards a more compact structure occurs during the initial stages of aggregation. Binding of A53T α-synuclein to a flavenoid based amyloid fibril inhibitor, (–)-epigallocatechin-3-gallate, has been observed with a 1:1 stoichiometry. By analysis of ion collision cross-sections, we show epigallocatechin gallate binding prevents protein conformational change, and in turn decreases the formation of fibrillar aggregates.

Download Full-text

Intermolecular Disulfide Linkages Are Not Required for Transthyretin Amyloid Fibril Formation in Vitro

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1993.2495 ◽

1993 ◽

Vol 197 (2) ◽

pp. 415-421 ◽

Cited By ~ 16

Author(s):

S.L. Mccutchen ◽

J.W. Kelly

Keyword(s):

Amyloid Fibril ◽

Fibril Formation ◽

Amyloid Fibril Formation ◽

Disulfide Linkages

Download Full-text

P4-284: Açaí (Euterpe oleraceae Mart) berry extract protects neuronal cells against beta-amyloid toxicity and inhibits beta-amyloid fibril formation in vitro

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.1677 ◽

2013 ◽

Vol 9 ◽

pp. P808-P808

Author(s):

Daphne Wong ◽

Scott Smid

Keyword(s):

Amyloid Fibril ◽

Neuronal Cells ◽

Beta Amyloid ◽

Fibril Formation ◽

Amyloid Toxicity ◽

Amyloid Fibril Formation

Download Full-text

Cerebrospinal fluid inhibits Alzheimer ?-amyloid fibril formation in vitro

Annals of Neurology ◽

10.1002/ana.410340422 ◽

1993 ◽

Vol 34 (4) ◽

pp. 631-633 ◽

Cited By ~ 43

Author(s):

Thomas Wisniewski ◽

Eduardo Castano ◽

Jorge Ghiso ◽

Blas Frangione

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Fibril ◽

Fibril Formation ◽

Amyloid Fibril Formation

Download Full-text

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms222111484 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11484

Author(s):

Masatoshi Inden ◽

Ayaka Takagi ◽

Hazuki Kitai ◽

Taisei Ito ◽

Hisaka Kurita ◽

...

Keyword(s):

Amyloid Fibril ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Therapeutic Agents ◽

Amyloid Fibril Formation ◽

Transcription Factor Eb

Aggregation of α-synuclein (α-Syn) is implicated in the pathogenesis of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Therefore, the removal of α-Syn aggregation could lead to the development of many new therapeutic agents for neurodegenerative diseases. In the present study, we succeeded in generating a new α-Syn stably expressing cell line using a piggyBac transposon system to investigate the neuroprotective effect of the flavonoid kaempferol on α-Syn toxicity. We found that kaempferol provided significant protection against α-Syn-related neurotoxicity. Furthermore, kaempferol induced autophagy through an increase in the biogenesis of lysosomes by inducing the expression of transcription factor EB and reducing the accumulation of α-Syn; thus, kaempferol prevented neuronal cell death. Moreover, kaempferol directly blocked the amyloid fibril formation of α-Syn. These results support the therapeutic potential of kaempferol in diseases such as synucleinopathies that are characterized by α-Syn aggregates.

Download Full-text