Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Muriel Arimon, Valerie Grimminger, Fausto Sanz, Hilal A. Lashuel

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The heat shock protein Hsp104 has been reported to possess the ability to modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (Aβ) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of Aβ. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of Aβ was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of Aβ in a concentration-dependent but ATP-independent manner. Inhibition of Aβ fibrillization by Hsp104 is observable up to Hsp104/Aβ stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of Aβ amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with Aβ protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric Aβ. Together, these findings suggest that the strong inhibition of Aβ fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.

Original languageEnglish
Pages (from-to)1157-1173
Number of pages17
JournalJournal of Molecular Biology
Volume384
Issue number5
DOIs
Publication statusPublished - 31 Dec 2008
Externally publishedYes

Fingerprint

Amyloid
Aptitude
Adenosine Triphosphate
Huntington Disease
Heat-Shock Proteins
Parkinson Disease
Seeds
Animal Models
Cell Culture Techniques
Yeasts
Escherichia coli
Proteins

Keywords

  • Alzheimer's disease
  • amyloid formation Aβ
  • disaggregation
  • Hsp104

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils. / Arimon, Muriel; Grimminger, Valerie; Sanz, Fausto; Lashuel, Hilal A.

In: Journal of Molecular Biology, Vol. 384, No. 5, 31.12.2008, p. 1157-1173.

Research output: Contribution to journalArticle

Arimon, Muriel ; Grimminger, Valerie ; Sanz, Fausto ; Lashuel, Hilal A. / Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils. In: Journal of Molecular Biology. 2008 ; Vol. 384, No. 5. pp. 1157-1173.
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