A toxic mutant huntingtin species is resistant to selective autophagy

Nat Chem Biol. 2017 Nov;13(11):1152-1154. doi: 10.1038/nchembio.2461. Epub 2017 Sep 4.

Abstract

Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity.

MeSH terms

  • Autophagy*
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Mutation*
  • Peptides / genetics
  • Polyubiquitin / metabolism
  • Protein Conformation
  • Proteolysis
  • Repetitive Sequences, Nucleic Acid
  • Ubiquitination

Substances

  • Huntingtin Protein
  • Peptides
  • Polyubiquitin
  • polyglutamine