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The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration.

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journal contribution
posted on 2022-05-05, 00:36 authored by Emma Perri, Colleen ThomasColleen Thomas, Sonam Parakh, Damian M Spencer, Julie AtkinJulie Atkin
The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and its dysregulation is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER) is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR), distinct signaling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulfide Isomerase (PDI) is an ER chaperone induced during ER stress that is responsible for the formation of disulfide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However, specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.


This work was supported by funding from the National Health and Medical Research Council of Australia (Project grants 1006141,1030513, and 1086887) and the Motor Neurone Disease Research Institute of Australia, Angie Cunningham Laugh to Cure MND Grant. EP is supported by an Australian Postgraduate Award scholarship.


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Frontiers in Cell and Developmental Biology



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Frontiers Media SA



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© 2016 Perri, Thomas, Parakh, Spencer and Atkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.