Lindahl Maria, Saarma Mart, Lindholm Päivi
Institute of Biotechnology, P.O.Box 56, Viikinkaari 5, FI-00014, University of Helsinki, Finland.
Institute of Biotechnology, P.O.Box 56, Viikinkaari 5, FI-00014, University of Helsinki, Finland.
Neurobiol Dis. 2017 Jan;97(Pt B):90-102. doi: 10.1016/j.nbd.2016.07.009. Epub 2016 Jul 15.
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote the survival of midbrain dopaminergic neurons which degenerate in Parkinson's disease (PD). However, CDNF and MANF are structurally and functionally clearly distinct from the classical, target-derived neurotrophic factors (NTFs) that are solely secreted proteins. In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) and evidence suggests that MANF, and possibly CDNF, is important for the maintenance of ER homeostasis. MANF expression is particularly high in secretory tissues with extensive protein production and thus a high ER protein folding load. Deletion of MANF in mice results in a diabetic phenotype and the activation of unfolded protein response (UPR) in the pancreatic islets. However, information about the intracellular and extracellular mechanisms of MANF and CDNF action is still limited. Here we will discuss the structural motifs and physiological functions of CDNF and MANF as well as their therapeutic potential for the treatment of neurodegenerative diseases and diabetes. Currently available knockout models of MANF and CDNF in mice, zebrafish and fruit fly will increase information about the biology of these interesting proteins.
脑源性多巴胺神经营养因子（CDNF）和中脑星形胶质细胞源性神经营养因子（MANF）可促进中脑多巴胺能神经元的存活，而这些神经元在帕金森病（PD）中会发生退化。然而，CDNF和MANF在结构和功能上与经典的、仅由靶标分泌的神经营养因子（NTF）明显不同。在细胞中，CDNF和MANF定位于内质网（ER），有证据表明MANF，可能还有CDNF，对维持内质网稳态很重要。MANF在具有大量蛋白质产生且内质网蛋白质折叠负荷高的分泌组织中表达特别高。在小鼠中删除MANF会导致糖尿病表型，并激活胰岛中的未折叠蛋白反应（UPR）。然而，关于MANF和CDNF作用的细胞内和细胞外机制的信息仍然有限。在这里，我们将讨论CDNF和MANF的结构基序和生理功能，以及它们在治疗神经退行性疾病和糖尿病方面的治疗潜力。目前在小鼠、斑马鱼和果蝇中可用的MANF和CDNF基因敲除模型将增加有关这些有趣蛋白质生物学特性的信息。
