PDF(Pubmed)
Abstract：
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
摘要：
RNA结合蛋白已成为许多神经退行性疾病机制中的核心参与者。特别是,在某些家族性肌萎缩侧索硬化症（ALS）和约10％的散发性额颞叶变性（FTLD）中，存在肉瘤融合蛋白病（FUS）。在这里，我们确定将超声处理的人FUS原纤维局灶性注射到ALS相关的突变体或野生型人FUS替代内源性小鼠FUS的小鼠大脑中足以诱导突变体和野生型FUS的局灶性细胞质错位和聚集，随着时间的推移扩散到大脑的远端区域。相对于野生型人FUS,由引起ALS的FUS突变体加速人源化FUS小鼠的小鼠脑中的人FUS原纤维诱导的FUS聚集。注射超声处理的人FUS原纤维不会诱导FUS聚集和随后在注射到仅含有小鼠FUS的原始小鼠大脑后扩散。表明人类FUS聚集及其朊病毒样传播的物种屏障。原纤维诱导的人FUS聚集体概括了FTLD的病理特征，包括FUS和TAF15和淀粉样蛋白样的洗涤剂不溶性增加，积累泛素和p62但不积累TDP-43的FUS的细胞质沉积物。最后,经超声处理的FUS原纤维的注射被证明会加剧突变人类FUS表达导致的年龄依赖性认知和行为缺陷。因此，FUS的局灶性接种聚集和通过朊病毒样传播进一步传播引起FUS蛋白病和FTLD样疾病进展。
