title: A multi-pathway perspective on protein aggregation: implications for control of the rate and extent of amyloid formation.
abstract: The nucleation-growth model has been used extensively for characterizing in vitro amyloid fibril formation kinetics and for simulating the relationship between amyloid and disease. In the majority of studies amyloid has been considered as the dominant, or sole, aggregation end product, with the presence of other competing non-amyloid aggregation processes, for example amorphous aggregate formation, being largely ignored. Here, we examine possible regulatory effects that off-pathway processes might exert on the rate and extent of amyloid formation - in particular their potential for providing false positives and negatives in the evaluation of anti-amyloidogenic agents. Furthermore, we investigate how such competing reactions might influence the standard interpretation of amyloid aggregation as a two-state system. We conclude by discussing our findings in terms of the general concepts of supersaturation and system metastability - providing some mechanistic insight as to how these empirical phenomena may manifest themselves in the amyloid arena.
authors: Research School of Chemistry, Australian National University, Acton, ACT 2601, Australia; Institute for Protein Research, Osaka University, 3-1-Yamada-oka, Suita, Osaka 565-0871, Japan. Electronic address: damien.hall@anu.edu.au.
authors: Damien
authors: D
authors: Hall
authors: MTA-ELTE NAP B Neuroimmunology Research Group and Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors: József
authors: J
authors: Kardos
authors: Laboratory of Biochemistry and Genetics, NIDDK, NIH, Bethesda, Bld 8, MD 20892-0830, USA.
authors: Herman
authors: H
authors: Edskes
authors: Research School of Chemistry, Australian National University, Acton, ACT 2601, Australia.
authors: John A
authors: JA
authors: Carver
authors: Institute for Protein Research, Osaka University, 3-1-Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Yuji
authors: Y
authors: Goto
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D058225:Plaque, Amyloid / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: Amorphous aggregation; Amyloid; Anti-amyloid ligand screen; Competition; Kinetic model; Regulation
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