Intranuclear Aggregation of Mutant FUS/TLS as a Molecular Pathomechanism of Amyotrophic Lateral Sclerosis
Intranuclear Aggregation of Mutant FUS/TLS as a Molecular Pathomechanism of Amyotrophic Lateral Sclerosis
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DOI：
10.1074/jbc.m113.516492
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发表时间：
2014-01-10
影响因子：
4.8
通讯作者：
Furukawa, Yoshiaki
中科院分区：
文献类型：
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作者：
Nomura, Takao;Watanabe, Shoji;Furukawa, Yoshiaki
FUS/TLS的显性突变导致家族型肌萎缩性侧索硬化症（fALS），其中细胞质中突变FUS蛋白的异常积累已被观察到是主要的病理改变。许多致病突变已被证明会恶化FUS的核定位信号，从而促进突变蛋白的细胞质错定位。然而，其他一些突变对培养细胞中FUS的核定位没有影响，它们在fALS的病理机制中的作用仍然不清楚。在这里，我们发现致病突变G156E显著增加体外和体内FUS聚集的倾向。在突变型而非野生型FUS中观察到自发的淀粉样蛋白样纤维聚集体的体外形成，值得注意的是，这些原纤维作为有效的种子，触发了野生型蛋白的聚集。此外，G156E突变不干扰FUS的核定位，但促进了大鼠海马神经元核内包涵体的形成，具有显著的细胞毒性。因此，我们提出由一组致病突变触发的FUS核内聚集是FUS相关fALS疾病的另一种病理机制。
Dominant mutations in FUS/TLS cause a familial form of amyotrophic lateral sclerosis (fALS), where abnormal accumulation of mutant FUS proteins in cytoplasm has been observed as a major pathological change. Many of pathogenic mutations have been shown to deteriorate the nuclear localization signal in FUS and thereby facilitate cytoplasmic mislocalization of mutant proteins. Several other mutations, however, exhibit no effects on the nuclear localization of FUS in cultured cells, and their roles in the pathomechanism of fALS remain obscure. Here, we show that a pathogenic mutation, G156E, significantly increases the propensities for aggregation of FUS in vitro and in vivo. Spontaneous in vitro formation of amyloid-like fibrillar aggregates was observed in mutant but not wild-type FUS, and notably, those fibrils functioned as efficient seeds to trigger the aggregation of wild-type protein. In addition, the G156E mutation did not disturb the nuclear localization of FUS but facilitated the formation of intranuclear inclusions in rat hippocampal neurons with significant cytotoxicity. We thus propose that intranuclear aggregation of FUS triggered by a subset of pathogenic mutations is an alternative pathomechanism of FUS-related fALS diseases.