1. Acta Neuropathol. 2008 Apr;115(4):479-89. Epub 2008 Jan 10.

Curcumin inhibits aggregation of alpha-synuclein.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE.

Department of Anatomy and Neurobiology, Washington University School of Medicine,
St Louis, MO 63110, USA.

Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in
Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is
structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid
and prevent further oligomerization of Abeta monomers onto growing amyloid
beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid
formation are similar in Parkinson's disease (PD) and AD, we investigated the
effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of
AS aggregation was developed by treatment of purified AS protein (wild-type) with
1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin
inhibited aggregation in a dose-dependent manner and increased AS solubility. The
aggregation-inhibiting effect of curcumin was next investigated in cell culture
utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in
which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and
its aggregation examined under different concentrations of curcumin. To estimate
aggregation in an unbiased manner, a protocol was developed in which the images
were captured automatically through a high-throughput cell-based screening
microscope. The obtained images were processed automatically for aggregates
within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant
alpha-synuclein aggregation was observed within 48 h subsequent to curcumin
addition. Our data suggest that curcumin inhibits AS oligomerization into higher
molecular weight aggregates and therefore should be further explored as a
potential therapeutic compound for PD and related disorders.


PMID: 18189141 [PubMed - indexed for MEDLINE]


1. J Biol Chem. 2004 Jun 25;279(26):26846-57. Epub 2004 Apr 19.

The flavonoid baicalein inhibits fibrillation of alpha-synuclein and
disaggregates existing fibrils.

Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL.

Department of Chemistry and Biochemistry, University of California, Santa Cruz,
California 95064, USA.

The aggregation of alpha-synuclein has been implicated as a critical step in the
development of Parkinson's disease. Parkinson's disease is a progressive
neurodegenerative disorder caused by the loss of dopaminergic neurons from the
substantia nigra; currently, no cure exists. Baicalein is a flavonoid with
antioxidant properties; upon oxidation, it forms several products including
quinones. We show here that low micromolar concentrations of baicalein, and
especially its oxidized forms, inhibit the formation of alpha-synuclein fibrils.
In addition, existing fibrils of alpha-synuclein are disaggregated by baicalein.
The product of the inhibition reaction is predominantly a soluble oligomer of
alpha-synuclein, in which the protein molecules have been covalently modified by
baicalein quinone to form a Schiff base with a lysine side chain in
alpha-synuclein. The binding of baicalein was abolished by conversion of the Tyr
residues into Phe, demonstrating that Tyr is involved in the interaction of
alpha-synuclein with baicalein. In disaggregation baicalein causes fragmentation
throughout the length of the fibril. These observations suggest that baicalein
and similar compounds may have potential as therapeutic leads in combating
Parkinson's disease and that diets rich in flavonoids may be effective in
preventing the disorder.


PMID: 15096521 [PubMed - indexed for MEDLINE]


1. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. Epub 2010 Apr 12.

EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces
cellular toxicity.

Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker
EE.

Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125
Berlin-Buch, Germany. jbiesch@mdc-berlin.de

Protein misfolding and formation of beta-sheet-rich amyloid fibrils or aggregates
is related to cellular toxicity and decay in various human disorders including
Alzheimer's and Parkinson's disease. Recently, we demonstrated that the
polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and
amyloid-beta fibrillogenesis. It associates with natively unfolded polypeptides
and promotes the self-assembly of unstructured oligomers of a new type. Whether
EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we
show that EGCG has the ability to convert large, mature alpha-synuclein and
amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic
to mammalian cells. Mechanistic studies revealed that the compound directly binds
to beta-sheet-rich aggregates and mediates the conformational change without
their disassembly into monomers or small diffusible oligomers. These findings
suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.


PMCID: PMC2867908
PMID: 20385841 [PubMed - indexed for MEDLINE]