近日，中国台湾Jun-An Chen研究团队合作发现小RNA17～92在运动神经元中扮演了抵御渐冻症的功能。这一研究成果于2019年8月发表在国际学术期刊《细胞—干细胞》上。

据了解，运动神经元(MN)的进展性退化是肌萎缩侧索硬化症(ALS)的特征。支配肢体的外侧运动神经柱的运动神经元（LMC-MN）似乎特别脆弱，在ALS患者中是最先受到影响的MN之一。

研究人员发现，这种敏感性的差异与发病前LMC-MN中mir-17～92簇的降低有关。在症状发生前SOD1 G93A小鼠的脊柱MN中，mir-17 ~ 92的降低伴随着核内PTEN的增加。退分化SOD1 G93A小鼠LMC-MN中mir-17 ~ 92/核PTEN信号轴的选择性失调，在双转基因的胚胎干细胞系统中被证实，即在人类SOD1+/L144F诱导的iPSC来源的MN中重现。进一步研究表明，mir-17 ~ 92的高表达显著挽救了SOD1+/ L144F的人类MN，并且腺相关病毒(AAV) 9-mir-17 ~ 92的鞘内递送能够改善运动神经的损伤并提高SOD1 G93A小鼠的生存。因此，mir-17 ~ 92在作为MN退分化的预后标志物和SOD1相关ALS的潜在治疗靶点中可能具有价值。

 

附：英文原文

Title: Mir-17～92 Confers Motor Neuron Subtype Differential Resistance to ALS-Associated Degeneration

Author: Ying-Tsen Tung, Kuan-Chih Peng, Yen-Chung Chen, Ya-Ping Yen, Mien Chang, Sebastian Thams, Jun-An Chen

Issue&Volume: Volume 25 Issue 2

Abstract: Progressive degeneration of motor neurons (MNs) is the hallmark of amyotrophic lateral sclerosis (ALS). Limb-innervating lateral motor column MNs (LMC-MNs) seem to be particularly vulnerable and are among the first MNs affected in ALS. Here, we report association of this differential susceptibility with reduced expression of the mir-17～92 cluster in LMC-MNs prior to disease onset. Reduced mir-17～92 is accompanied by elevated nuclear PTEN in spinal MNs of presymptomatic SOD1 G93A mice. Selective dysregulation of the mir-17～92/nuclear PTEN axis in degenerating SOD1 G93A LMC-MNs was confirmed in a double-transgenic embryonic stem cell system and recapitulated in human SOD1 +/L144F-induced pluripotent stem cell (iPSC)-derived MNs. We further show that overexpression of mir-17～92 significantly rescues human SOD1 +/L144F MNs, and intrathecal delivery of adeno-associated virus (AAV)9- mir-17～92 improves motor deficits and survival in SOD1 G93A mice. Thus, mir-17～92 may have value as a prognostic marker of MN degeneration and is a candidate therapeutic target in SOD1-linked ALS.

DOI: https://doi.org/10.1016/j.stem.2019.04.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30165-1