The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications |
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| Authors: | Gerwyn Morris Basant K. Puri Ken Walder Michael Berk Michael Maes André F. Carvalho |
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| Affiliation: | 1.Tir Na Nog,Llanelli,UK;2.IMPACT Strategic Research Centre, School of Medicine,Deakin University,Geelong,Australia;3.Department of Medicine, Imperial College London,Hammersmith Hospital,London,UK;4.The Centre for Molecular and Medical Research, School of Medicine,Deakin University,Geelong,Australia;5.Department of Psychiatry,University of Melbourne,Melbourne,Australia;6.Orygen, the National Centre of Excellence in Youth Mental Health,Parkville,Australia;7.Centre for Youth Mental Health,University of Melbourne,Melbourne,Australia;8.Florey Institute for Neuroscience and Mental Health,Melbourne,Australia;9.Physiotherapy Department,South London and Maudsley NHS Foundation Trust,London,UK;10.Health Service and Population Research Department,Institute of Psychiatry, Psychology and Neuroscience, King’s College London,London,UK;11.Faculty of Health, Social Care and Education,Anglia Ruskin University,Chelmsford,UK;12.Department of Psychiatry,Chulalongkorn University,Bangkok,Thailand;13.Department of Psychiatry, Faculty of Medicine,University of Toronto,Toronto,Canada;14.Centre for Addiction & Mental Health (CAMH),Toronto,Canada |
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| Abstract: | The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted. |
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