ER stress and the unfolded protein response in neurodegeneration

Key Points

  • Many neurodegenerative diseases involve the accumulation of protein aggregates

  • Endoplasmic reticulum (ER) stress triggers activation of the unfolded protein response (UPR), an adaptive reaction that restores cellular protein homeostasis, known as proteostasis

  • Dysfunction of proteostasis is associated with abnormal levels of ER stress and is associated with neuronal degeneration in human post-mortem brain tissue

  • Targeting the UPR can have distinct and even opposite effects on disease progression, depending on the disease context and the signalling branch that is analysed

  • Gene therapy and pharmacological strategies to attenuate ER stress alleviates degeneration in various disease models

  • Chronic ER stress not only results in neuronal loss, but also represses the synthesis of synaptic proteins, with implications for cognition and memory, and possibly autism spectrum disorder

Abstract

The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network — particularly disturbances to the function of endoplasmic reticulum (ER) — are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.

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Figure 1: Protein aggregates in tissue from patients with neurodegenerative disease.
Figure 2: ER stress and proteostasis in neurodegenerative diseases.
Figure 3: Unfolded protein response pathways and interventions.
Figure 4: Mechanisms that trigger ER stress in neurodegenerative disease.

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Acknowledgements

C.H. is supported by the FONDAP program 15150012, the US Office of Naval Research-Global (ONR-G) N62909-16-1-2003, the Millennium Institute P09-015-F, FONDEF ID16I10223, FONDEF D11E1007, the US Air Force Office of Scientific Research FA9550-16-1-0384, CONICYT-Brazil 441921/2016-7, the ALS Therapy Alliance 2014-F-059, the Muscular Dystrophy Association 382453, the Michael J Fox Foundation for Parkinson's Research – Target Validation grant No 9277, FONDECYT no. 1140549, and the ALSRP Therapeutic Idea Award AL150111. S.S. is supported by the Synapsis Foundation, Stiftung UNISCIENTIA, the Frick foundation for ALS research, Swiss National Science Foundation and European Research Council 725825.

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Functional impact of ER stress on neuroinflammation and axonal damage. (PDF 107 kb)

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Glossary

Autophagy

Self-degradation process with functions that include the removal of misfolded or aggregated proteins and damaged organelles.

Proteostasis

A portmanteau of the words protein and homeostasis, referring to the function of integrated biological pathways within cells that control the biogenesis, folding, trafficking and degradation of proteins present within and outside the cell.

ER stress

A cellular condition that involves accumulation of misfolded and/or unfolded proteins at the ER; ER stress activates the unfolded protein response, which enables adaptation to stress or triggers apoptosis of irreversibly-damaged cells.

Unfolded protein response

A signal transduction pathway that is activated by an accumulation of unfolded or misfolded proteins in the ER lumen; the unfolded protein response mediates adaptation to protein folding stress or the elimination of non-functional cells by apoptosis.

ER-associated degradation

Cellular pathway that targets misfolded proteins at the ER for ubiquitylation and subsequent degradation in the cytosol by the proteasome.

Integrated stress response

An adaptive pathway in eukaryotic cells that is activated by a range of stress conditions that converge on phosphorylation of eukaryotic translation initiation factor 2α, which leads to a decrease in global protein synthesis and the upregulation of selected genes that promote cellular homeostasis.

Protein disulfide isomerase

One of a family of enzymes in the ER that catalyse the formation, isomerization and breakage of disulfide bonds between cysteine residues within proteins as they fold, enabling the correct arrangement of disulfide bonds in the fully folded state to form quickly.

Hormesis

A phenomenon in which an agent that is toxic to a biological system at high doses has beneficial effects on that system at lower doses.

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Hetz, C., Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13, 477–491 (2017). https://doi.org/10.1038/nrneurol.2017.99

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