Journal
LABORATORY INVESTIGATION
Volume 100, Issue 9, Pages 1197-1207Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41374-020-0436-1
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Funding
- Ono Pharmaceutical Co Ltd
- National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [DK112921, DK020579]
- National Center for Advancing Translational Sciences (NCATS) of the NIH [TR002065, TR000448]
- Washington University Diabetes Research Center - NIDDK of the NIH
- Manpei Suzuki Diabetes Foundation
- JSPS Overseas Research Fellowships
- NIH [F30DK111070]
- Washington University Institute of Clinical and Translational Sciences from the NCATS of the NIH [UL1TR002345]
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Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated beta cell death and enhances beta cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome. Wolfram syndrome is a prototype of endoplasmic reticulum (ER) stress disorder characterized by diabetes, visual impairment, and neurodegeneration. Currently, there is no treatment that can halt or reverse the disease progression. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor-based regenerative gene therapy is an emerging therapeutic strategy for Wolfram syndrome and other ER stress-related disorders.
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