The RNA binding protein (RBP) RBM45 forms nuclear and cytoplasmic inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), and Alzheimer’s disease (AD). The normal functions of RBM45 are poorly understood, as are the mechanisms by which it forms inclusions in disease. To better understand the normal and pathological functions of RBM45, we evaluated whether the protein functions via association with several membraneless organelles and whether such an association could promote the formation of nuclear RBM45 inclusions. Under basal conditions, RBM45 is diffusely distributed throughout the nucleus and does not localize to membraneless organelles, including nuclear speckles, Cajal bodies, or nuclear gems. During cellular stress, however, nuclear RBM45 undergoes a reversible, RNA-binding dependent incorporation into nuclear stress bodies (NSBs). Chronic stress leads to the persistent association of RBM45 with NSBs and the irreversible accumulation of nuclear RBM45 inclusions. We also quantified the cell type- and disease-specific patterns of RBM45 pathology in ALS, FTLD-TDP, and AD. RBM45 nuclear and cytoplasmic inclusions are found in both neurons and glia in ALS, FTLD-TDP, and AD but are absent in non-neurologic disease controls. Across neurodegenerative diseases, RBM45 nuclear inclusion pathology occurs more frequently than cytoplasmic RBM45 inclusion pathology and exhibits cell type-specific variation. Collectively, our results define new stress-associated functions of RBM45, a mechanism for nuclear RBM45 inclusion formation, a role for NSBs in the pathogenesis of ALS, FTLD-TDP, and AD, and further underscore the importance of protein self-association to both the normal and pathological functions of RBPs in these diseases.

中文翻译：

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RBM45与核应力体结合，并在慢性细胞应力和神经退行性疾病中形成核内含物。

RNA结合蛋白（RBP）RBM45在肌萎缩性侧索硬化症（ALS），额颞叶变性伴TDP-43蛋白病（FTLD-TDP）和阿尔茨海默氏病（AD）中形成神经元和神经胶质中的核和细胞质内含物。人们对RBM45的正常功能以及在疾病中形成包涵体的机制了解甚少。为了更好地了解RBM45的正常和病理功能，我们评估了蛋白质是否通过与几个无膜细胞器的结合而起作用，以及这种结合是否可以促进核RBM45内含物的形成。在基础条件下，RBM45分散地分布在整个核中，并且不局限于无膜细胞器，包括核斑点，Cajal体或核宝石。但是，在细胞紧张期间，核RBM45经历可逆的，RNA依赖性依赖性整合入核应激体（NSB）。慢性应激导致RBM45与NSB的持续结合以及核RBM45内含物的不可逆积累。我们还定量了ALS，FTLD-TDP和AD中RBM45病理学的细胞类型和疾病特异性模式。在ALS，FTLD-TDP和AD的神经元和神经胶质中都发现了RBM45核和胞质内含物，但在非神经系统疾病对照中则没有。在整个神经退行性疾病中，RBM45核内包涵体病变的发生率比细胞质的RBM45内涵体病变更为频繁，并且表现出特定于细胞类型的变异。总的来说，我们的研究结果定义了RBM45与压力相关的新功能，RBM45核包裹体形成的机制，NSB在ALS发病机理中的作用，