Institute of Biotechnology, Viikinkaari 9, Viikki Biocenter, University of Helsinki, 00014 Helsinki, Finland.
Dev Neurobiol. 2010 Apr;70(5):360-71. doi: 10.1002/dneu.20760.
Current therapeutic interventions for neurodegenerative diseases alleviate only disease symptoms, while treatments that could stop or reverse actual degenerative processes are not available. Parkinson's disease (PD) is a movement disorder with characteristic degeneration of dopaminergic neurons in the midbrain. Few neurotrophic factors (NTFs) that promote survival, maintenance, and differentiation of affected brain neurons are considered as potential therapeutic agents for the treatment of neurodegenerative diseases. Thus, it is important to search and study new NTFs that could also be used in therapy. In this review, we discuss novel evolutionary conserved family of NTFs consisting of two members in the vertebrates, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Invertebrates, including Drosophila and Caenorhabditis have a single protein homologous to vertebrate CDNF/MANF. Characteristic feature of these proteins is eight structurally conserved cysteine residues, which determine the protein fold. The crystal structure analysis revealed that CDNF and MANF consist of two domains; an amino-terminal saposin-like domain that may interact with lipids or membranes, and a presumably unfolded carboxy-terminal domain that may protect cells against endoplasmic reticulum stress. CDNF and MANF protect midbrain dopaminergic neurons and restore motor function in 6-hydroxydopamine rat model of PD in vivo. In line, Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly, suggesting that the function of CDNF/MANF proteins is evolutionary conserved. Future studies will reveal the receptors and mode of action of these novel factors, which are potential therapeutic proteins for the treatment of PD.
目前用于神经退行性疾病的治疗干预措施仅能缓解疾病症状，而无法阻止或逆转实际的退行性过程。帕金森病（PD）是一种运动障碍，其特征是中脑多巴胺能神经元的退化。一些促进受影响脑神经元存活、维持和分化的神经营养因子（NTFs）被认为是治疗神经退行性疾病的潜在治疗剂。因此，寻找和研究新的 NTFs 也很重要，这些 NTFs也可以用于治疗。在这篇综述中，我们讨论了一种新的进化保守的 NTF 家族，该家族由脊椎动物中的两个成员组成，即脑源性多巴胺神经营养因子（CDNF）和中脑神经胶质衍生的神经营养因子（MANF）。无脊椎动物，包括果蝇和秀丽隐杆线虫，有一种与脊椎动物 CDNF/MANF 同源的单一蛋白质。这些蛋白质的特征是八个结构保守的半胱氨酸残基，决定了蛋白质的折叠。晶体结构分析表明，CDNF 和 MANF 由两个结构域组成；一个氨基末端类 Saposin 样结构域，可能与脂质或膜相互作用，和一个假定的无折叠羧基末端结构域，可能保护细胞免受内质网应激。CDNF 和 MANF 可保护中脑多巴胺能神经元，并在体内 6-羟多巴胺诱导的 PD 大鼠模型中恢复运动功能。与此一致的是，果蝇 MANF 对于维持多巴胺能神经突和多巴胺水平是必需的，这表明 CDNF/MANF 蛋白的功能在进化上是保守的。未来的研究将揭示这些新型因子的受体和作用模式，它们是治疗 PD 的潜在治疗蛋白。
