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Updated: Jun 27, 2026

Growth Assays to Assess Polyglutamine Toxicity in Yeast
09:06

Growth Assays to Assess Polyglutamine Toxicity in Yeast

Published on: March 5, 2012

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

Martin L Duennwald1, Susan Lindquist

  • 1The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

Genes & Development
|November 19, 2008
PubMed

Insights

Protein misfolding causes neurodegenerative diseases like Huntington's disease (HD). This study reveals that polyglutamine (polyQ) expansion impairs endoplasmic reticulum-associated degradation (ERAD), a key protein quality control pathway, contributing to toxicity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Protein misfolding is implicated in neurodegenerative diseases.
  • Abnormally long polyglutamine (polyQ) expansions in proteins cause disorders like Huntington's disease (HD).
  • The precise triggers of polyQ toxicity remain unclear despite known cellular pathway impairments in HD.

Purpose of the Study:

  • To investigate the early cellular defects caused by polyQ-expanded huntingtin (htt) fragments.
  • To elucidate the mechanisms underlying polyQ toxicity in neurodegenerative conditions.
  • To identify potential therapeutic targets for polyQ-related disorders.

Main Methods:

  • Utilized yeast and neuron-like PC12 cells expressing polyQ-expanded htt fragments.
  • Assessed endoplasmic reticulum (ER)-associated degradation (ERAD) function.
  • Investigated the interaction between polyQ-expanded htt and ERAD components (Npl4, Ufd1, p97).

Main Results:

  • PolyQ-expanded htt fragments caused a specific and drastic defect in ERAD in both yeast and PC12 cells.
  • The essential ERAD proteins Npl4, Ufd1, and p97 were found to be entrapped by polyQ-expanded htt fragments.
  • Overexpression of Npl4 and Ufd1 alleviated polyQ toxicity in these cellular models.

Conclusions:

  • Impaired ER protein homeostasis is a significant and conserved contributor to polyQ toxicity.
  • ERAD dysfunction is an early and critical event in polyQ-induced neurodegeneration.
  • Targeting ERAD components may offer a therapeutic strategy for Huntington's disease and other polyQ disorders.

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