What Can the Kinetics of Amyloid Fibril Formation Tell about Off-pathway Aggregation?

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Rosa Crespo (Author) FEUP; Eva Villar-Alvarez (Author) Other; Pablo Taboada (Author) Other; Fernando A. Rocha (Author) FEUP; Ana M. Damas (Author) Other; Pedro M. Martins (Author) FEUP

Journal

Title: Journal of Biological Chemistry

Vol. 291 No. 4

Pages: 2018-2032

ISSN: 0021-9258

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 26 Citations

Associated Projects

PTDC/BIA-PRO/101260/2008 - Crescimento de Cristais de Proteínas com Propriedades de Difracção de Raios-X de Elevada Qualidade

LEPABE - Laboratório de Engenharia de Processos, Ambiente, Biotecnologia e Energia

Other information

Authenticus ID: P-00K-4P0

DOI: 10.1074/jbc.m115.699348

Abstract (EN): Some of the most prevalent neurodegenerative diseases are characterized by the accumulation of amyloid fibrils in organs and tissues. Although the pathogenic role of these fibrils has not been completely established, increasing evidence suggests off-pathway aggregation as a source of toxic/detoxicating deposits that still remains to be targeted. The present work is a step toward the development of off-pathway modulators using the same amyloid-specific dyes as those conventionally employed to screen amyloid inhibitors. We identified a series of kinetic signatures revealing the quantitative importance of off-pathway aggregation relative to amyloid fibrillization; these include nonlinear semilog plots of amyloid progress curves, highly variable end point signals, and half-life coordinates weakly influenced by concentration. Molecules that attenuate/intensify the magnitude of these signals are considered promising off-pathway inhibitors/promoters. An illustrative example shows that amyloid deposits of lysozyme are only the tip of an iceberg hiding a crowd of insoluble aggregates. Thoroughly validated using advanced microscopy techniques and complementary measurements of dynamic light scattering, CD, and soluble protein depletion, the new analytical tools are compatible with the high-throughput methods currently employed in drug discovery.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15