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Trophic activities of endoplasmic reticulum proteins CDNF and MANF

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Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are endoplasmic reticulum (ER) luminal proteins that confer trophic activities in a wide range of tissues under diverse pathological conditions. Despite initially being classified as neurotrophic factors, neither protein structurally nor functionally resembles bona fide neurotrophic factors. Their highly homologous structures comprise a unique globular, saposin-like domain within the N-terminus joined by a flexible linker to a C-terminus containing a SAP-like domain, CXXC motif and an ER retention sequence. Neurotrophic factors exert effects by binding to cognate receptors in the plasma membrane; however, no cell surface receptors have been identified for MANF and CDNF. Both can act as unfolded protein response (UPR) genes that modulate the UPR and inflammatory processes. The trophic activity of MANF and CDNF extends beyond the central nervous system with MANF being crucial for the development of pancreatic β cells and both have trophic effects in a variety of diseases related to the liver, heart, skeletal tissue, kidney and peripheral nervous system. In this article, the unique features of MANF and CDNF, such as their structure and mechanisms of action related to ER stress and inflammation, will be reviewed. Recently identified interactions with lipids and membrane trafficking will also be described. Lastly, their function and therapeutic potential in different diseases including a recent clinical trial using CDNF to treat Parkinson’s disease will be discussed. Collectively, this review will highlight MANF and CDNF as broad-acting trophic factors that regulate functions of the endoplasmic reticulum.

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Acknowledgements

This work was supported by the Intramural Research Program of the NIH, NIDA. The authors thank Dr. Mark Henderson, Dr. Kathleen Trychta, Dr. Deon Harvey, Ms. Lacey Kennedy and Ms. Helena Baffoe-Bonnie for their comments on the manuscript. We also thank Ms. Katie Nolan for her comments and assistance preparing Fig. 1.

Funding

This work was supported by the Intramural Research Program of the NIH, NIDA.

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  1. Molecular Mechanisms of Cellular Stress and Inflammation Lab, Intramural Research Program, National Institute on Drug Abuse, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA

    Maria Jӓntti & Brandon K. Harvey

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  1. Maria Jӓntti
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Correspondence to Brandon K. Harvey.

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Jӓntti, M., Harvey, B.K. Trophic activities of endoplasmic reticulum proteins CDNF and MANF. Cell Tissue Res 382, 83–100 (2020). https://doi.org/10.1007/s00441-020-03263-0

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