TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations
TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations
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DOI：
10.1172/jci97103
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发表时间：
2018-03-01
影响因子：
15.9
通讯作者：
Udd, Bjarne
中科院分区：
文献类型：
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作者：
Lee, YouJin;Jonson, Per Harald;Udd, Bjarne
多系统蛋白质病（MSP）涉及应激颗粒（SG）动力学和自噬蛋白降解的紊乱，其是影响肌肉、脑和骨的一系列退行性疾病的发病机制的基础。具体来说，自噬适配器SQSTM 1中的相同突变可导致4种不同表型的不同突变：肌萎缩性侧索硬化症（ALS）、额颞叶痴呆、佩吉特骨病和远端肌病。它已被假设，临床多效性涉及到额外的遗传决定因素，但到目前为止，证据一直缺乏。在这里，我们提供的证据表明，WV（p.N357S）变异决定了一个肌肉退行性表型时，继承，沿着致病性SQSTMI突变。在实验上，TIA 1-N357 S变体显著增强了体外液-液相分离，并损害了活细胞中的SG动力学。SQSTM 1的耗尽或SQSTM 1的突变版本的引入类似地损害SG动力学。TIA 1-N357 S-持续性SG与SQSTM 1、泛素缀合物的积累和其他聚集蛋白的关联增加。TIA 1-N357 S变体和SQSTM 1-A390 X突变在成肌细胞中的协同表达导致相对于对照成肌细胞受损的SG清除和肌毒性。这些发现表明SG稳态和泛素介导的自噬降解之间存在致病性联系，这种联系驱动MSP表型的突变。
Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a WV (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTMI mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.