A Huntingtin-Mediated Fast Stress Response Halting Endosomal Trafficking Is Defective in Huntington's Disease

Hum Mol Genet. 2015 Jan 15;24(2):450-62. doi: 10.1093/hmg/ddu460. Epub 2014 Sep 8.

Abstract

Cellular stress is a normal part of the aging process and is especially relevant in neurodegenerative disease. Canonical stress responses, such as the heat shock response, activate following exposure to stress and restore proteostasis through the action of isomerases and chaperones within the cytosol. Through live-cell imaging, we demonstrate involvement of the Huntington's disease (HD) protein, huntingtin, in a rapid cell stress response that lies temporally upstream of canonical stress responses. This response is characterized by the formation of distinct cytosolic puncta and reversible localization of huntingtin to early endosomes. The formation of these puncta, which we have termed huntingtin stress bodies (HSBs), is associated with arrest of early-to-recycling and early-to-late endosomal trafficking. The critical domains for this response have been mapped to two regions of huntingtin flanking the polyglutamine tract, and we observe polyglutamine-expanded huntingtin-expressing cells to be defective in their ability to recover from this stress response. We propose that HSB formation rapidly diverts high ATP use from vesicular trafficking during stress, thus mobilizing canonical stress responses without relying on increased energy metabolism, and that restoration from this response is defective in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Endosomes / genetics
  • Endosomes / metabolism*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / physiopathology*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Transport
  • Stress, Physiological

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins