Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer.
Protein conformational changes that result in misfolding, aggregation and amyloid fibril formation are a common feature of many neurodegenerative disorders. Studies with beta-amyloid (Abeta), alpha-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 Abeta and alpha-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.
Wacker
Jennifer L
JL
Department of Pharmacology, University of Washington, Seattle, Washington, 98195-2120, USA.
Zareie
M Hadi
MH
Fong
Hanson
H
Sarikaya
Mehmet
M
Muchowski
Paul J
PJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000939:Epitopes / Q000276:immunology; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D012995:Solubility
D000939:Epitopes; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine; D012967:Sodium Dodecyl Sulfate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases