期刊
NATURE REVIEWS NEUROLOGY
卷 13, 期 8, 页码 477-491出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nrneurol.2017.99
关键词
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资金
- FONDAP [15150012]
- US Office of Naval Research-Global (ONR-G) [N62909-16-1-2003]
- Millennium Institute [P09-015-F]
- FONDEF [ID16I10223, D11E1007]
- US Air Force Office of Scientific Research [FA9550-16-1-0384]
- CONICYT-Brazil [441921/2016-7]
- ALS Therapy Alliance [2014-F-059]
- Muscular Dystrophy Association [382453]
- Michael J Fox Foundation for Parkinson's Research - Target Validation [9277]
- FONDECYT [1140549]
- ALSRP Therapeutic Idea Award [AL150111]
- Synapsis Foundation
- Stiftung UNISCIENTIA
- Frick foundation for ALS research
- Swiss National Science Foundation
- European Research Council [725825]
- European Research Council (ERC) [725825] Funding Source: European Research Council (ERC)
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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