Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin

Patrick Lajoie, Erik L. Snapp

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Huntington's disease (HD) is caused by expanded glutamine repeats within the huntingtin (Htt) protein. Mutant Htt (mHtt) in the cytoplasm has been linked to induction of the luminal endoplasmic reticulum (ER) stress pathway, the unfolded protein response (UPR). How mHtt impacts the susceptibility of the ER lumen to stress remains poorly understood. To investigate molecular differences in the ER in cells expressing mHtt, we used live-cell imaging of a sensitive reporter of the misfolded secretory protein burden, GFP fused to the ER chaperone BiP (also known as GRP78), which decreases in mobility as it binds increasing amounts of misfolded proteins. Striatal neurons expressing full-length mHtt showed no differences in BiP-GFP mobility and no evidence of UPR activation compared with wild-type cells at steady state. However, mHtt-expressing cells were acutely sensitive to misfolded secretory proteins. Treatment with ER stressors, tunicamycin or DTT, rapidly decreased BiP-GFP mobility in mHtt striatal cells and accelerated UPR activation compared with wild-type cells. mHtt-expressing cells exhibited decreased misfolded protein flux as a result of ER associated degradation (ERAD) dysfunction. Furthermore, UPR-adapted mHtt cells succumbed to misfolded protein stresses that could be tolerated by adapted wild-type cells. Thus, mHtt expression impairs misfolded secretory protein turnover, decreases the ER stress threshold, and increases cell vulnerability to insults.

Original languageEnglish (US)
Pages (from-to)3332-3343
Number of pages12
JournalJournal of Cell Science
Volume124
Issue number19
DOIs
StatePublished - Oct 1 2011

Fingerprint

Endoplasmic Reticulum Stress
Hypersensitivity
Unfolded Protein Response
Endoplasmic Reticulum
Corpus Striatum
Proteins
Endoplasmic Reticulum-Associated Degradation
Tunicamycin
Huntington Disease
Heat-Shock Proteins
Glutamine
Cytoplasm
Neurons

Keywords

  • Bip
  • ERAD
  • FRAP
  • Huntingtin
  • UPR

ASJC Scopus subject areas

  • Cell Biology

Cite this

Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin. / Lajoie, Patrick; Snapp, Erik L.

In: Journal of Cell Science, Vol. 124, No. 19, 01.10.2011, p. 3332-3343.

Research output: Contribution to journalArticle

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