Department of Functional Anatomy and Neuroscience, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, 351-0198, Japan.
Neurochem Res. 2019 Jun;44(6):1279-1288. doi: 10.1007/s11064-018-2665-x. Epub 2018 Oct 24.
Our understanding of the physiological relevance of unique Damage-induced neuronal endopeptidase (DINE) [also termed Endothelin-converting enzyme-like 1 (ECEL1)] has recently expanded. DINE/ECEL1 is a type II membrane-bound metalloprotease, belonging to a family including the neprilysin (NEP) and endothelin-converting enzyme (ECE). The family members degrade and/or process peptides such as amyloid β and big-endothelins, which are closely associated with pathological conditions. Similar to NEP and ECE, DINE has been expected to play an important role in injured neurons as well as in developing neurons, because of its remarkable transcriptional response to neuronal insults and predominant neuronal expression from the embryonic stage. However, the physiological significance of DINE has long remained elusive. In the last decade, a series of genetically manipulated mice have driven research progress to elucidate the physiological aspects of DINE. The mice ablating Dine fail to arborize the embryonic motor axons in some subsets of muscles, including the respiratory muscles, and die immediately after birth. The abnormal phenotype of motor axons is also caused by one amino acid exchanges of DINE/ECEL1, which are responsible for distal arthrogryposis type 5 in a group of human congenital movement disorders. Furthermore, the mature Dine-deficient mice in which the lethality is rescued by genetic manipulation have shown the involvement of DINE in central nervous system regeneration. Here we describe recent research advances that DINE-mediated proteolytic processes are critical for nerve development, regeneration and pathogenesis, and discuss the future potential for DINE as a therapeutic target for axonal degeneration/disorder.
我们对独特的损伤诱导神经元内肽酶（DINE）[也称为内皮素转换酶样 1（ECEL1）]的生理相关性的理解最近有所扩展。DINE/ECEL1 是一种 II 型膜结合金属蛋白酶，属于包括神经肽酶（NEP）和内皮素转换酶（ECE）在内的家族。家族成员降解和/或加工肽，如淀粉样蛋白β和大内皮素，这些肽与病理状况密切相关。与 NEP 和 ECE 相似，由于其对神经元损伤的显著转录反应以及从胚胎期开始的主要神经元表达，DINE 有望在受伤神经元和发育中的神经元中发挥重要作用。然而，DINE 的生理意义长期以来一直难以捉摸。在过去的十年中，一系列基因敲除小鼠的研究推动了阐明 DINE 生理方面的研究进展。在一些肌肉亚群中，包括呼吸肌，缺失 Dine 的小鼠胚胎运动轴突无法分枝，并且在出生后立即死亡。运动轴突的异常表型也由 DINE/ECEL1 的一个氨基酸交换引起，该交换负责一组人类先天性运动障碍中的远端关节挛缩症 5 型。此外，通过基因操作挽救致死性的成熟 Dine 缺陷型小鼠表明 DINE 参与中枢神经系统再生。在这里，我们描述了最近的研究进展，即 DINE 介导的蛋白水解过程对于神经发育、再生和发病机制至关重要，并讨论了 DINE 作为治疗轴突变性/障碍的潜在治疗靶点的未来潜力。
