Abstract
Protein conformational changes that result in misfolding, aggregation and amyloid fibril formation are a common feature of many neurodegenerative disorders. Studies with β-amyloid (Aβ), α-synuclein and other amyloid-forming proteins indicate that the assembly of misfolded protein conformers into fibrils is a complex process that may involve the population of metastable spherical and/or annular oligomeric assemblies. Here, we show by atomic force microscopy that a mutant huntingtin fragment with an expanded polyglutamine repeat forms spherical and annular oligomeric structures reminiscent of those formed by Aβ and α-synuclein. Notably, the molecular chaperones Hsp70 and Hsp40, which are protective in animal models of neurodegeneration, modulate polyglutamine aggregation reactions by partitioning monomeric conformations and disfavoring the accretion of spherical and annular oligomers.
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Acknowledgements
P.J.M. is supported by the US National Institute of Neurological Disorders and Stroke (R01NS47237), by a US National Institutes of Health (NIH) construction award (C06 RR 14571), by the Alzheimer's Disease Research Center at the University of Washington and by the Hereditary Disease Foundation under the auspices of the Cure Huntington's Disease Initiative. J.L.W. is funded in part by PHS NRSA T32 GM07270 from the US National Institute of General Medical Sciences. H.F., M.H.Z. and M.S. thank DURINT Program for support. AFM experiments were carried out in the Molecular Biomimetics Facilities at the University of Washington. We thank P. Patterson for the MW1-8 antibodies, S. Finkbeiner for the 3B5H10 antibody and M. Mayer and K. Terada for plasmids.
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Supplementary information
Supplementary Fig. 1
Three-dimensional topography of a HD53Q annular structure. (PDF 131 kb)
Supplementary Fig. 2
Hsp70 or Hsp40 alone does not destabilize HD53Q oligomers. (PDF 919 kb)
Supplementary Fig. 3
Reactivity of MW7 to HD20Q does not change over time or in the presence of Hsp70 and Hsp40. (PDF 483 kb)
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Wacker, J., Zareie, M., Fong, H. et al. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 11, 1215–1222 (2004). https://doi.org/10.1038/nsmb860
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DOI: https://doi.org/10.1038/nsmb860
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