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 TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 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.

中文翻译：

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TIA1 变体在具有 SQSTM1 突变的多系统蛋白病中驱动肌变性

多系统蛋白病 (MSP) 涉及应激颗粒 (SG) 动力学紊乱和自噬蛋白降解，这是影响肌肉、大脑和骨骼的一系列退行性疾病的发病机制的基础。具体而言，自噬衔接子 SQSTM1中的相同突变可导致 4 种不同表型的不同外显率：肌萎缩侧索硬化 (ALS)、额颞叶痴呆、Paget 骨病和远端肌病。据推测，临床多效性与其他遗传决定因素有关，但迄今为止，证据不足。在这里，我们提供的证据表明，TIA1 (p.N357S) 变异在遗传时决定了肌退行性表型，以及致病性SQSTM1突变。在实验上，TIA1-N357S 变体显着增强了体外液-液-相分离并损害了活细胞中的 SG 动力学。SQSTM1 的耗尽或 SQSTM1 的突变版本的引入同样会损害 SG 动力学。TIA1-N357S–持久性 SG 增加了与 SQSTM1 的关联、泛素结合物的积累和额外的聚集蛋白。相对于对照成肌细胞，TIA1-N357S 变体和 SQSTM1-A390X 突变在成肌细胞中的协同表达导致受损的 SG 清除和肌毒性。这些发现证明了 SG 稳态与泛素介导的自噬降解之间的致病联系，后者驱动了 MSP 表型的外显率。