Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway.
Dopamine (DA) and alpha-synuclein (alpha-SN) are two key molecules associated with Parkinson's disease (PD). We have identified a novel action of DA in the initial phase of alpha-SN aggregation and demonstrate that DA induces alpha-SN to form soluble, SDS-resistant oligomers. The DA:alpha-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 alpha-SN, causing an alteration to the structure of the protein. Furthermore, DA inhibited the formation of iron-induced alpha-SN amyloidogenic aggregates, suggesting that DA acts as a dominant modulator of alpha-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.
Cappai
Roberto
R
Department of Pathology, The University of Melbourne, Victoria, Australia. r.cappai@unimelb.edu.au
Leck
Su-Ling
SL
Tew
Deborah J
DJ
Williamson
Nicholas A
NA
Smith
David P
DP
Galatis
Denise
D
Sharples
Robyn A
RA
Curtain
Cyril C
CC
Ali
Feda' E
FE
Cherny
Robert A
RA
Culvenor
Janetta G
JG
Bottomley
Stephen P
SP
Masters
Colin L
CL
Barnham
Kevin J
KJ
Hill
Andrew F
AF
D000682:Amyloid / Q000737:chemistry; D052160:Benzothiazoles; D002942:Circular Dichroism; D004298:Dopamine / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D006801:Humans; D010300:Parkinson Disease / Q000209:etiology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology*; D013844:Thiazoles / Q000032:analysis; D051844:alpha-Synuclein / Q000737:chemistry*
D000682:Amyloid; D052160:Benzothiazoles; D005290:Ferric Compounds; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate; D004298:Dopamine