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.

中文翻译：

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FUS 种子聚集和传播引起的额颞叶痴呆样疾病进展


RNA 结合蛋白已成为许多神经退行性疾病机制中的核心角色。特别是，肉瘤融合蛋白病 (FUS) 存在于一些家族性肌萎缩侧索硬化症 (ALS) 病例中，以及约 10% 的散发性额颞叶变性 (FTLD) 病例中。在这里，我们确定，将超声处理的人类 FUS 原纤维局部注射到小鼠大脑中，其中 ALS 相关突变体或野生型人类 FUS 取代​​内源性小鼠 FUS，足以诱导突变体和野生型 FUS 的局部细胞质错误定位和聚集，随着时间的推移，扩散到大脑的远端区域。相对于野生型人类 FUS，引起 ALS 的 FUS 突变体加速了人源化 FUS 小鼠大脑中人类 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，并且在注射到仅含有小鼠 FUS 的幼稚小鼠大脑后不会引起 FUS 聚集和随后的扩散，这表明对人 FUS 聚集及其朊病毒样扩散存在物种屏障。原纤维诱导的人 FUS 聚集体重现了 FTLD 的病理特征，包括 FUS 和 TAF15 的去污剂不溶性增加，以及 FUS 的淀粉样蛋白样细胞质沉积物积累泛素和 p62，但不积累 TDP-43。最后，注射超声处理的 FUS 原纤维会加剧突变型人类 FUS 表达导致的年龄依赖性认知和行为缺陷。因此，FUS 的局灶性种子聚集和通过朊病毒样扩散的进一步传播引起 FUS 蛋白病和 FTLD 样疾病进展。