The neurotransmitter serotonin interrupts α-synuclein amyloid maturation

Indolic derivatives can affect fibril growth of amyloid forming proteins. The neurotransmitter serotonin (5-HT) is of particular interest, as it is an endogenous molecule with a possible link to neuropsychiatric symptoms of Parkinson disease. A key pathomolecular mechanism of Parkinson disease is the misfolding and aggregation of the intrinsically unstructured protein alpha-synuclein. We performed a biophysical study to investigate an influence between these two molecules. In an isolated in vitro system, 5-HT interfered with alpha-synuclein amyloid fiber maturation, resulting in the formation of partially structured. SDS-resistant intermediate aggregates. The C-terminal region of alpha-synuclein was essential for this interaction, which was driven mainly by electrostatic forces. 5-HT did not bind directly to monomeric alpha-synuclein molecules and we propose a model where 5-HT interacts with early intermediates of alpha-synuclein amyloidogenesis, which disfavors their further conversion into amyloid fibrils. (C) 2011 Elsevier B.V. All rights reserved.