New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis
New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis
复制标题
DOI：
10.1007/s11064-018-2665-x
复制
发表时间：
2019-06-01
影响因子：
4.4
通讯作者：
Kiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Kiryu-Seo, Sumiko;Nagata, Kenichi;Kiyama, Hiroshi
我们对独特的损伤诱导的神经元内肽酶（DINE）[也称为内皮素转换酶样1 (ECEL1)]的生理相关性的理解最近得到了扩展。DINE/ECEL1是一种II型膜结合金属蛋白酶，属于一个家族，包括NEP和内皮素转换酶（ECE）。家族成员降解和/或加工肽，如淀粉样蛋白和大内皮素，这与病理状况密切相关。与NEP和ECE类似，DINE被认为在损伤神经元和发育神经元中发挥重要作用，因为它对神经元损伤有显著的转录反应，并且从胚胎阶段起就主要表达神经元。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，一系列转基因小鼠推动了研究进展，以阐明DINE的生理方面。在一些肌肉亚群（包括呼吸肌）中，切除Dine的小鼠未能切断胚胎运动轴突，并在出生后立即死亡。运动轴突的异常表型也是由DINE/ECEL1的一个氨基酸交换引起的，这是一组人类先天性运动障碍中5型远端关节挛缩的原因。此外，通过基因操作挽救其致死率的成熟缺碘小鼠表明，DINE参与中枢神经系统再生。在这里，我们描述了DINE介导的蛋白水解过程对神经发育、再生和发病机制至关重要的最新研究进展，并讨论了DINE作为轴突变性/疾病治疗靶点的未来潜力。
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 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.