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Pathogenic mechanisms
A16 Endoplasmic reticulum stress: an initiator of neuroinflammation in Huntington's disease?
  1. K R Ayasolla,
  2. R K Kalathur,
  3. M E Futschik
  1. Centre for Molecular and Structural Biomedicine, University of Algarve, Campus de Gambelas, Faro, Portugal

Abstract

Background The endoplasmic reticulum (ER) is a crucial organelle for correct folding and modification of numerous proteins. Accumulation of unfolded or misfolded protein causes a stress signal in the ER. To ensure fidelity of protein folding, several transcriptional and translational mechanisms are activated during the unfolded protein response (UPR). The main function of the UPR is re-establishing homeostasis by increasing the folding capacity. Recent studies, however, have suggested that ER stress and activated UPR are interconnected with inflammatory processes (K Zhang, RJ Kaufman. Nature 2008).

Aims In this study, we explore the intriguing possibility that ER stress is an initiator of neuroinflammation in HD and is thereby crucially contributing to degeneration of neuronal tissue.

Methods We have conducted a critical review of the accumulated evidence of inflammation induced by ER stress in neurodegenerative diseases in general and in HD specifically. Additionally, we scrutinised publically accessible data sets for molecular mechanisms linking ER stress, UPR and neuroinflammation.

Results Several independent lines of evidence indicate that ER stress can mediate inflammatory responses and can enhance neurodegeneration. Notably, secreted inflammatory cytokines and activated microglia cells could be a possible mechanism leading to axonal damage and extensive neuronal cell death in HD patients. Using a systems biology approach, we developed explicit models for the interconnection between ER stress and neuroinflammation. Based on these models, we propose a defined set of follow-up experiments to further clarify the role of inflammatory signalling in HD.

Conclusions The conducted review points to several mechanisms linking ER stress to inflammation and degeneration of neuronal tissue in Huntington's disease. We hope that the suggested experimental studies can ultimately lead to the development of novel HD drug therapeutics.

  • endoplasmic reticulum stress (ER stress)
  • unfolded protein response (UPR)
  • neuroinflammation
  • neurodegenerative disease
  • inflammatory cytokine
  • microglia
  • therapeutics

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