Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases

Nature Reviews Neuroscience volume 15, pages233–249(2014)Cite this article

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Abstract

The unfolded protein response (UPR) is a homeostatic mechanism by which cells regulate levels of misfolded proteins in the endoplasmic reticulum (ER). Although it is well characterized in non-neuronal cells, a proliferation of papers over the past few years has revealed a key role for the UPR in normal neuronal function and as an important driver of neurodegenerative diseases. A complex scenario is emerging in which distinct UPR signalling modules have specific and even opposite effects on neurodegeneration depending on the disease context. Here, we provide an overview of the most recent findings addressing the biological relevance of ER stress in the nervous system.

Key Points

  • Equilibrated protein homeostasis (referred to as proteostasis) requires the dynamic coordination of efficient folding of newly synthesized proteins, quality control and degradative mechanisms to reduce the load of unfolded and/or misfolded proteins and thereby prevent abnormal protein aggregation. In response to proteostasis perturbations, the folding and/or degrading capacity of the endoplasmic reticulum (ER) is dynamically adjusted by the induction of a complex signalling network known as the unfolded protein response (UPR).

  • Most neurodegenerative diseases are considered to be protein misfolding disorders. They have distinct clinical manifestations, but they all involve the accumulation of abnormally folded proteins in the form of small oligomers, aggregates or large-protein inclusions. Disturbance of several aspects of proteostasis contributes to the progression of these neurodegenerative diseases.

  • Perturbation of ER function or the UPR may be part of the aetiology of several diseases; that is, disease proteins may directly or indirectly perturb the UPR machinery and alter the function of the secretory pathway at different levels, resulting in irreversible alterations in neuronal proteostasis and degeneration.

  • UPR activation can either enhance or reduce neurodegeneration. UPR adaptive responses or pro-apoptotic programmes are possibly triggered depending on the load of misfolded proteins and the specific UPR signalling mechanisms that are activated.

  • An ER adaptive response can engage a preconditioning stage by adjusting proteostasis in neurons but can also propagate cell-non-autonomously in the whole organism to maintain global proteostasis and limit ageing. Physiological perturbation of the ER through the engagement of adaptive ER-hormetic mechanisms could be exploited to develop therapeutic strategies that attenuate neurodegeneration.

  • UPR pathways have physiological functions in different aspects of brain development and function, such as CNS development, learning, memory and hypothalamic functions.

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Figure 1: UPR signalling pathways in mammals.
Figure 2: UPR signalling outputs and neurodegeneration.
Figure 3: Disturbance of ER homeostasis in neurodegenerative diseases.
Figure 4: The role of the UPR in brain physiology.

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Acknowledgements

The authors apologize to all colleagues whose work could not be cited owing to space limitations. We thank G. Martinez, V. H. Cornejo and C. Levet for the initial figure design. This work was funded by FONDECYT 1140549, Millennium Institute No. P09-015-F, Ring Initiative ACT1109, FONDEF grant No. D11I1007, CONICYT grant USA2013-0003, ECOS-CONICYTC13S02, the ALS Therapy Alliance, the Muscular Dystrophy Association and the Alzheimer´s Disease Association (C.H.), in addition to grants from the CNRS (ANR LipidinRetina and Ire1-PD), the Fondation de France and the Fondation ARC pour la recherche sur le cancer (B.M.).

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Affiliations

  1. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    • Claudio Hetz

  2. Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, University of Chile, Santiago, Chile

    • Claudio Hetz

  3. Neurounion Biomedical Foundation, Santiago, Chile

    • Claudio Hetz

  4. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    • Claudio Hetz

  5. Laboratory of Molecular Biology of the Cell, CNRS UMR5239, Ecole Normale Supérieure de Lyon, UMS3444 Biosciences Lyon Gerland, University of Lyon, Lyon, 69364, France

    • Bertrand Mollereau

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Hetz, C., Mollereau, B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15, 233–249 (2014) doi:10.1038/nrn3689

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