Hofmeister Salts and Potential Therapeutic Compounds Accelerate in Vitro Fibril Formation of the N-Terminal Domain of PABPN1 Containing a Disease-Causing Alanine Extension

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• 作者：Grit Lodderstedt ; Rolf Sachs ; Jü ; rgen Faust ; Frank Bordusa ; Uwe Kü ; hn ; Ralph Golbik ; Andreas Kerth ; Elmar Wahle ; Jochen Balbach ; Elisabeth Schwarz
• 刊名：Biochemistry
• 出版年：2008
• 出版时间：February 19, 2008
• 年：2008
• 卷：47
• 期：7
• 页码：2181 - 2189
• 全文大小：316K
• 年卷期：v.47,no.7(February 19, 2008)
• ISSN：1520-4995

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.