systematic in vivo analysis of the intrinsic determinants of amyloid β pathogenicity系统的体内淀粉样β致病性的内在决定因素的分析.pdf

PLoS BIOLOGY Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid b Pathogenicity 1 1 1 1 1,2,3 4 Leila M. Luheshi , Gian Gaetano Tartaglia , Ann-Christin Brorsson , Amol P. Pawar , Ian E. Watson , Fabrizio Chiti , Michele Vendruscolo1 5,6 1 3,5* , David A. Lomas , Christopher M. Dobson , Damian C. Crowther 1 Department of Chemistry, University of Cambridge, Cambridge, United Kingdom, 2 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom, ` 3 Department of Genetics, University of Cambridge, Cambridge, United Kingdom, 4 Dipartimento di Scienze Biochimiche, Universita degli Studi di Firenze, Firenze, Italy, 5 Department of Medicine, University of Cambridge, Cambridge, United Kingdom, 6 Cambridge Institute for Medical Research, Cambridge, United Kingdom Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Ab42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Ab42