The stress rheostat: an interplay between the unfolded protein response (UPR) and autophagy in neurodegeneration

Curr Mol Med. 2008 May;8(3):157-72. doi: 10.2174/156652408784221324.

Abstract

The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under conditions of endoplasmic reticulum (ER) stress. The UPR controls diverse processes such as protein folding, secretion, ER biogenesis, protein quality control and macroautophagy. Occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation, including Amyotrophic lateral sclerosis, Prion-related disorders, and conditions such as Parkinson's, Huntington's, and Alzheimer's disease. Strong correlations are observed between disease progression, accumulation of protein aggregates, and induction of the UPR in animal and in vitro models of neurodegeneration. In addition, the first reports are available describing the engagement of ER stress responses in brain post-mortem samples from human patients. Despite such findings, the role of the UPR in the central nervous system has not been addressed directly and its contribution to neurodegeneration remains speculative. Recently, however, pharmacological manipulation of ER stress and autophagy - a stress pathway modulated by the UPR - using chemical chaperones and autophagy activators has shown therapeutic benefits by attenuating protein misfolding in models of neurodegenerative disease. The most recent evidence addressing the role of the UPR and ER stress in neurodegenerative disorders is reviewed here, along with therapeutic strategies to alleviate ER stress in a disease context.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Autophagy*
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Models, Biological
  • Nerve Degeneration / metabolism
  • Neurodegenerative Diseases / metabolism*
  • Parkinson Disease / metabolism
  • Protein Folding*
  • Stress, Physiological / metabolism

Substances

  • Membrane Proteins