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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/11294
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| Title: | The tale of the tail of MANF: ER calcium homeostasis as a therapeutic target |
| Authors: | Harvey, BK;Trychta, KA;Back, SM;Dossat, AM;Yan, S;Anttila, J;Wu, KJ;Airavaara, M;Wang, Y;Henderson, M |
| Contributors: | Center for Neuropsychiatric Research |
| Abstract: | Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress response protein capable of promoting neuroprotection and neurore-generation. We conducted structure and function studies of the various protein domains of MANF and found the C- terminal tail (ASARTDL) is necessary and sufficient for ER localization. We also found the tail is mediating secretion in response to the depletion of calcium in the ER. ER calcium stores are important for many cellular functions, such as protein folding, lipid metabolism, and signaling pathways. Disruption of ER calcium homeostasis is implicated in multiple neurological diseases, including stroke, Parkinson’s disease, and Alzheimer’s disease. Using the tail of MANF, we developed a secreted ER calcium modulated protein (SERCaMP) to monitor ER calcium depletion in both in vitro and in vivo disease models. We created a Gaussia luciferase (GLuc)-ASARTDL SERCaMP reporter and showed that oxygenglucose deprivation caused ER calcium depletion and decreased cell viability. Treatment with the ryanodine receptor antagonist dantrolene attenuated secretion of our reporter and increased cell viability in vitro. Intracranial adenoassociated virus (AAV)-GLuc-SERCaMP-injected rats showed evidence of ER calcium depletion following occlusion of the middle cerebral artery and dantrolene treatment reduced the infarction volume. Lastly, we developed a high throughput screen based on our GLuc-SERCaMP reporter and identified novel drugs for stabilizing ER calcium and improving recovery from oxygen-glucose deprivation. Our data support a model in which stroke causes ER calcium depletion and suggests that dantrolene can be used to reduce ER calcium depletion and improve the outcome from ischemic damage. |
| Date: | 2018-04 |
| Relation: | Cell Transplantation. 2018 Apr;27(4, Suppl. SI):696. |
| Link to: | https://doi.org/10.1177/0963689718765742 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0963-6897&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000438559500041 |
| Appears in Collections: | [其他] 會議論文/會議摘要
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| ISI000438559500041.pdf | 35Kb | Adobe PDF | 283 | View/Open |
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