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Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer

Jennifer L Wacker1, M Hadi Zareie, Hanson Fong

  • 1Department of Pharmacology, University of Washington, Seattle, Washington, 98195-2120, USA.

Nature Structural & Molecular Biology
|November 16, 2004
PubMed

Insights

Mutant huntingtin forms spherical and annular oligomers, similar to amyloid-beta. Molecular chaperones Hsp70 and Hsp40 reduce these toxic protein aggregates, offering neuroprotection.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Protein misfolding and aggregation into amyloid fibrils are hallmarks of neurodegenerative diseases.
  • Oligomeric protein assemblies, including spherical and annular structures, are implicated in disease pathogenesis.
  • Mutant huntingtin with expanded polyglutamine repeats is central to Huntington's disease.

Purpose of the Study:

  • To investigate the oligomeric structures formed by a mutant huntingtin fragment.
  • To determine the effect of molecular chaperones Hsp70 and Hsp40 on polyglutamine aggregation.

Main Methods:

  • Atomic force microscopy (AFM) was used to visualize protein structures.
  • Studies focused on a mutant huntingtin fragment with an expanded polyglutamine repeat.

Main Results:

  • Mutant huntingtin fragments formed spherical and annular oligomeric structures, similar to those observed with amyloid-beta and alpha-synuclein.
  • Hsp70 and Hsp40 modulated polyglutamine aggregation by stabilizing monomeric forms.
  • These chaperones inhibited the formation of spherical and annular oligomers.

Conclusions:

  • Mutant huntingtin aggregation follows pathways similar to other amyloidogenic proteins.
  • Hsp70 and Hsp40 exhibit protective effects by interfering with toxic oligomer formation.
  • Targeting chaperone activity may offer therapeutic strategies for Huntington's disease and related disorders.

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