Sprunger Macy L, Lee Ken, Sohn Brian S, Jackrel Meredith E
Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
iScience. 2022 Feb 11;25(3):103900. doi: 10.1016/j.isci.2022.103900. eCollection 2022 Mar 18.
Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear condensates in yeast. Disease-associated mutations in MATR3 impair condensate dynamics and disrupt condensate morphology. MATR3 toxicity is largely driven by its RNA-recognitions motifs (RRMs). Further, deletion of one or both RRMs drives coalescence of these condensates. Aberrant phase separation of several different RBPs underpins ALS/FTD, and we have engineered Hsp104 variants to reverse this misfolding. Here, we demonstrate that these same variants also counter MATR3 toxicity. We suggest that these Hsp104 variants which rescue MATR3, TDP-43, and FUS toxicity might be employed against a range of ALS/FTD-associated proteins. We anticipate that our yeast model could be a useful platform to screen for modulators of MATR3 misfolding.
Matrin-3（MATR3）是一种与DNA和RNA结合的蛋白质，与肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和远端肌病有关。在此，我们报告了MATR3蛋白毒性和聚集酵母模型的构建。MATR3在酵母中具有毒性，并形成动态的壳状核凝聚物。MATR3中的疾病相关突变会损害凝聚物动力学并破坏凝聚物形态。MATR3毒性很大程度上由其RNA识别基序（RRMs）驱动。此外，缺失一个或两个RRMs会促使这些凝聚物合并。几种不同的RNA结合蛋白（RBPs）的异常相分离是ALS/FTD的基础，我们已经设计了Hsp104变体来逆转这种错误折叠。在此，我们证明这些相同的变体也能对抗MATR3毒性。我们认为，这些能够挽救MATR3、TDP-43和FUS毒性的Hsp104变体可能可用于对抗一系列与ALS/FTD相关的蛋白质。我们预计我们的酵母模型可能是筛选MATR3错误折叠调节剂的有用平台。
