Falsone S Fabio, Leitinger Gerd, Karner Anita, Kungl Andreas J, Kosol Simone, Cappai Roberto, Zangger Klaus
Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
Biochim Biophys Acta. 2011 May;1814(5):553-61. doi: 10.1016/j.bbapap.2011.02.008. Epub 2011 Mar 2.
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 α-synuclein. We performed a biophysical study to investigate an influence between these two molecules. In an isolated in vitro system, 5-HT interfered with α-synuclein amyloid fiber maturation, resulting in the formation of partially structured, SDS-resistant intermediate aggregates. The C-terminal region of α-synuclein was essential for this interaction, which was driven mainly by electrostatic forces. 5-HT did not bind directly to monomeric α-synuclein molecules and we propose a model where 5-HT interacts with early intermediates of α-synuclein amyloidogenesis, which disfavors their further conversion into amyloid fibrils.
吲哚衍生物可影响淀粉样蛋白形成蛋白的纤维生长。神经递质5-羟色胺（5-HT）尤其引人关注，因为它是一种内源性分子，可能与帕金森病的神经精神症状有关。帕金森病的一个关键病理分子机制是内在无序蛋白α-突触核蛋白的错误折叠和聚集。我们进行了一项生物物理研究，以探究这两种分子之间的相互影响。在一个分离的体外系统中，5-HT干扰了α-突触核蛋白淀粉样纤维的成熟，导致形成部分结构化、耐十二烷基硫酸钠的中间聚集体。α-突触核蛋白的C末端区域对于这种相互作用至关重要，这种相互作用主要由静电力驱动。5-HT不直接与单体α-突触核蛋白分子结合，我们提出了一个模型，其中5-HT与α-突触核蛋白淀粉样变的早期中间体相互作用，这不利于它们进一步转化为淀粉样纤维。
