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.

中文翻译：

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内质网蛋白CDNF和MANF的营养活性

中脑星形胶质细胞源性神经营养因子 (MANF) 和脑多巴胺神经营养因子 (CDNF) 是内质网 (ER) 管腔蛋白，它们在多种病理条件下赋予多种组织营养活动。尽管最初被归类为神经营养因子，但蛋白质在结构和功能上都不像真正的神经营养因子。它们的高度同源结构包括一个独特的球状、saposin 样结构域，位于 N 端，通过一个灵活的接头连接到包含 SAP 样结构域、CXXC 基序和 ER 保留序列的 C 端。神经营养因子通过与质膜中的同源受体结合发挥作用；然而，尚未确定 MANF 和 CDNF 的细胞表面受体。两者都可以作为调节 UPR 和炎症过程的未折叠蛋白反应 (UPR) 基因。MANF 和 CDNF 的营养活性超出了中枢神经系统，其中 MANF 对胰腺 β 细胞的发育至关重要，并且在与肝脏、心脏、骨骼组织、肾脏和周围神经系统相关的各种疾病中都具有营养作用。在本文中，将回顾 MANF 和 CDNF 的独特特征，例如它们与 ER 应激和炎症相关的结构和作用机制。还将描述最近发现的与脂质和膜运输的相互作用。最后，将讨论它们在不同疾病中的功能和治疗潜力，包括最近使用 CDNF 治疗帕金森病的临床试验。集体，