Ozimski Lauren L, Sabater-Arcis Maria, Bargiela Ariadna, Artero Ruben
Translational Genomics Group, Incliva Health Research Institute, Avda. Menéndez Pelayo 4 acc., Valencia, 46010, Spain.
University Institute for Biotechnology and Biomedicine, Dr. Moliner 50, Burjasot, Valencia, 46100, Spain.
Biol Rev Camb Philos Soc. 2021 Apr;96(2):716-730. doi: 10.1111/brv.12674. Epub 2020 Dec 2.
Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3' untranslated region (3'UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind-like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav-like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin-proteasome activity, which may also be affected in DM1 by AMP-activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis-regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor-inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non-coding RNA metabolism, calcium dysregulation, and repeat-associated non-ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.
1型强直性肌营养不良（DM1）是成人中最常见的肌营养不良形式，但目前尚无治疗方法。尽管这种疾病会引发多系统症状，但其主要特征是肌病或肌肉病变，包括肌肉无力、萎缩和肌强直，严重影响着全球患者的生活。在分子水平上，DM1是由DM1蛋白激酶（DMPK）基因3'非翻译区（3'UTR）中的CTG重复序列扩增引起的，当这些序列转录成RNA时会形成由自身互补CUG发夹结构组成的核糖核蛋白病灶，这些结构能够结合蛋白质，从而导致致病性。这会导致肌肉盲样（MBNL）蛋白家族被隔离，使其耗尽，同时CUGBP Elav样家族成员1（CELF1）异常稳定，其水平升高。传统上，DM1研究主要集中在这种RNA毒性以及它如何改变MBNL和CELF1作为关键剪接调节因子的功能。然而，其他蛋白质也会受到有毒DMPK RNA的影响，并且有强有力的证据支持各种信号级联在DM1发病机制中发挥重要作用。具体而言，DM1中蛋白激酶B（AKT）信号传导的受损会增加自噬、凋亡和泛素 - 蛋白酶体活性，而腺苷酸活化蛋白激酶（AMPK）的下调也可能在DM1中影响这些过程。AKT还通过影响CELF1的亚细胞定位直接调节CELF1，并且通过抑制糖原合酶激酶3β（GSK3β）间接调节CELF1，而GSK3β在DM1中会稳定CELF1的抑制形式。另一种导致CELF1调节异常（在这种情况下是通过过度磷酸化）的激酶是蛋白激酶C（PKC）。此外，已经证明成纤维细胞生长因子诱导蛋白14（Fn14）在DM1中被诱导，并且与通过核因子κB（NFκB）途径的下游信号传导相关，将炎症与这种疾病联系起来。此外，MBNL1和CELF1在参与DM1肌病的细胞质过程中发挥作用，改变蛋白质稳态和肌节结构。最后，还有许多其他因素可能导致DM1中的肌肉表型，如卫星细胞的改变、非编码RNA代谢、钙调节异常以及重复相关的非ATG（RAN）翻译。本综述旨在整理目前关于DM1中受影响的不同途径的分散知识，并讨论那些可能有助于为DM1研究提供新治疗靶点但尚未探索的联系。
