Trophic activities of endoplasmic reticulum proteins CDNF and MANF
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REVIEW
Trophic activities of endoplasmic reticulum proteins CDNF and MANF Maria Jӓntti 1 & Brandon K. Harvey 1 Received: 10 May 2020 / Accepted: 20 July 2020 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
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. Keywords MANF . CDNF . UPR . ER stress . Inflammation
Discovery of MANF and CDNF as trophic factors Neurotrophic factors are secreted proteins that regulate neuronal development, plasticity, and survival. The first neurotrophic factor, nerve growth factor (NGF), has been studied since the 1940s (reviewed in Levi-Montalcini 1987) and was sequenced in 1971 (Angeletti and Bradshaw 1971). Other neurotrophic factors include brain-derived neurotrophic factor (BDNF), glial cell line–derived neurotrophic factor (GDNF) and neurotrophins (NT3–7). All these neurotrophic factors are secreted from a cell and bind to receptors on the plasma membrane such as tropomyosin receptor kinase (Trk) family
* Brandon K. Harvey [email protected] 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
receptors, p75NTR and GDNF family receptor α (GFR α) (Huang and Reichardt 2001; Airaksinen and Saarma 2002). Most of thes
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