文摘
The analysis of modulation of fibril formation helps to understand the mechanism of fibrillationprocesses besides opening routes for therapeutic intervention. Fibril formation was investigated with theN-terminal domain of the nuclear poly-A binding protein PABPN1, a protein in which mutation-basedalanine extensions lead to the disease oculopharyngeal muscular dystrophy (OPMD). The disease ischaracterized by fibrillar inclusions consisting mainly of PABPN1. A systematic modulation of fibrilformation kinetics was studied with trifluoroethanol, inorganic salts, low molecular weight organicsubstances, a poly-alanine peptide and anti-amyloidogenic compounds. Anions with salting out propertiesat high molar concentrations, poly-ethylene glycol and the poly-alanine peptide enhanced fibril formationrates. The effect of L-arginine on fibrillation rates depended on the counterion. Doxycycline and trehalose,compounds that have been found to mitigate OPMD symptoms in animal models, surprisingly acceleratedfibril formation. Our results suggest that in the case of salts, primarily the salting out effects rather thanelectrostatic effects modulate fibril formation. The unexpected acceleration of fibril formation by trehaloseand doxycycline questions the general view that these compounds per se impair fibril formation.