Conformational switch of polyglutamine-expanded huntingtin into benign aggregates leads to neuroprotective effect

Sci Rep. 2015 Oct 9:5:14992. doi: 10.1038/srep14992.

Abstract

The abundant accumulation of inclusion bodies containing polyglutamine-expanded mutant huntingtin (mHTT) aggregates is considered as the key pathological event in Huntington's disease (HD). Here, we demonstrate that FKBP12, an isomerase that exhibits reduced expression in HD, decreases the amyloidogenicity of mHTT, interrupts its oligomerization process, and structurally promotes the formation of amorphous deposits. By combining fluorescence-activated cell sorting with multiple biophysical techniques, we confirm that FKBP12 reduces the amyloid property of these ultrastructural-distinct mHTT aggregates within cells. Moreover, the neuroprotective effect of FKBP12 is demonstrated in both cellular and nematode models. Finally, we show that FKBP12 also inhibit the fibrillization process of other disease-related and aggregation-prone peptides. Our results suggest a novel function of FKBP12 in ameliorating the proteotoxicity in mHTT, which may shed light on unraveling the roles of FKBP12 in different neurodegenerative diseases and developing possible therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloid / ultrastructure
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cell Line, Tumor
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Microscopy, Confocal
  • Mutation*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Peptides / genetics*
  • Protein Aggregates / genetics
  • Protein Conformation
  • Tacrolimus Binding Protein 1A / genetics*
  • Tacrolimus Binding Protein 1A / metabolism
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • Amyloid
  • HTT protein, human
  • Huntingtin Protein
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Peptides
  • Protein Aggregates
  • polyglutamine
  • Tacrolimus Binding Protein 1A