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Dopamine promotes α‐synuclein aggregation into SDS‐resistant soluble oligomers via a distinct folding pathway
Author(s) -
Cappai Roberto,
Leck SuLing,
Tew Deborah J.,
Williamson Nicholas A.,
Smith David P.,
Galatis Denise,
Sharpies Robyn A.,
Curtain Cyril C.,
Ali Feda' E.,
Cherny Robert A.,
Culvenor Janetta G.,
Bottomley Stephen P.,
Masters Colin L.,
Barnham Kevin J.,
Hill Andrew F.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3437fje
Subject(s) - alpha synuclein , fibril , circular dichroism , thioflavin , oligomer , chemistry , biophysics , protein aggregation , amyloid (mycology) , protein folding , folding (dsp implementation) , dopamine , neurodegeneration , biochemistry , crystallography , parkinson's disease , alzheimer's disease , biology , disease , medicine , inorganic chemistry , organic chemistry , pathology , neuroscience , electrical engineering , engineering
ABSTRACT Dopamine (DA) and α‐synuclein (α‐SN) are two key molecules associated with Parkinson's disease (PD). We have identified a novel action of DA in the initial phase of α‐SN aggregation and demonstrate that DA induces α‐SN to form soluble, SDS‐resistant oligomers. The DA:α‐SN oligomeric species are not amyloidogenic as they do not react with thioflavin T and lack the typical amyloid fibril structures as visualized with electron microscopy. Circular dichroism studies indicate that in the presence of lipid membranes DA interacts with α‐SN, causing an alteration to the structure of the protein. Furthermore, DA inhibited the formation of iron‐induced α‐SN amyloidogenic aggregates, suggesting that DA acts as a dominant modulator of α‐SN aggregation. These observations support the paradigm emerging for other neurodegenerative diseases that the toxic species is represented by a soluble oligomer and not the insoluble fibril.