title: A multistage pathway for human prion protein aggregation in vitro: from multimeric seeds to β-oligomers and nonfibrillar structures.
abstract: Aberrant protein aggregation causes numerous neurological diseases including Creutzfeldt-Jakob disease (CJD), but the aggregation mechanisms remain poorly understood. Here, we report AFM results on the formation pathways of β-oligomers and nonfibrillar aggregates from wild-type full-length recombinant human prion protein (WT) and an insertion mutant (10OR) with five additional octapeptide repeats linked to familial CJD. Upon partial denaturing, seeds consisting of 3-4 monomers quickly appeared. Oligomers of ~11-22 monomers then formed through direct interaction of seeds, rather than by subsequent monomer attachment. All larger aggregates formed through association of these β-oligomers. Although both WT and 10OR exhibited identical aggregation mechanisms, the latter oligomerized faster due to lower solubility and, hence, thermodynamic stability. This novel aggregation pathway has implications for prion diseases as well as others caused by protein aggregation.
authors.affiliation: Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
authors.forename: Kang R
authors.initials: KR
authors.lastname: Cho
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Yu
authors.forename: Shaoman
authors.initials: S
authors.lastname: Yin
authors.forename: Marco
authors.initials: M
authors.lastname: Plomp
authors.forename: S Roger
authors.initials: SR
authors.lastname: Qiu
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.forename: Janet
authors.initials: J
authors.lastname: Moradian-Oldak
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.forename: James J
authors.initials: JJ
authors.lastname: De Yoreo
mesh_terms: D006801:Humans; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010316:Particle Size; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D011328:Prions