Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation.
Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation.
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DOI：
10.1186/s13024-021-00477-w
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发表时间：
2021-09-06
影响因子：
15.1
通讯作者：
Dupuis L
中科院分区：
文献类型：
--
作者：
Sanjuan-Ruiz I;Govea-Perez N;McAlonis-Downes M;Dieterle S;Megat S;Dirrig-Grosch S;Picchiarelli G;Piol D;Zhu Q;Myers B;Lee CZ;Cleveland DW;Lagier-Tourenne C;Da Cruz S;Dupuis L
FUS是一种RNA结合蛋白，参与RNA代谢的多个步骤，其突变与最严重的肌萎缩侧索硬化症（ALS）相关。细胞质FUS的积累可能是FUS突变毒性的主要原因。因此，防止FUS蛋白质的细胞质错误定位可能是一种有价值的治疗策略。FUS与其自身的前mRNA结合，产生一个自动调节环，通过多种提出的机制（包括保留内含子6和/或7）有效地缓冲FUS过量。在这里，我们引入了一个野生型FUS基因等位基因，保留所有的内含子序列，在小鼠的杂合或纯合表达的胞质保留FUS蛋白（Fus p53 NLS）先前被证明挑起ALS样疾病或出生后致死性，分别。野生型FUS完全挽救了由两个FUS FUSNLS等位基因引起的早期致死性，并改善了由突变型FUS FUSNLS杂合表达引起的年龄依赖性运动缺陷和寿命缩短。从机制上讲，野生型FUS降低了细胞质FUS的负荷，增加了内源性小鼠Fus mRNA中内含子6和7的保留，并降低了突变体mRNA的表达。因此，野生型FUS等位基因激活稳态自动调节环，维持恒定的FUS水平并减少细胞质中的突变蛋白。这些结果提供了一个概念的证据，一个自我调节能力的野生型FUS表达可以防止这种毁灭性的，目前难治性的，神经退行性疾病。在线版本包含补充材料，可通过10.1186/s13024-021-00477-w获得。
Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease. The online version contains supplementary material available at 10.1186/s13024-021-00477-w.
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影响因子：
14.9
作者：
Koyama A;Sugai A;Kato T;Ishihara T;Shiga A;Toyoshima Y;Koyama M;Konno T;Hirokawa S;Yokoseki A;Nishizawa M;Kakita A;Takahashi H;Onodera O
通讯作者：
Onodera O
影响因子：
12.7
作者：
Mitchell JC;McGoldrick P;Vance C;Hortobagyi T;Sreedharan J;Rogelj B;Tudor EL;Smith BN;Klasen C;Miller CC;Cooper JD;Greensmith L;Shaw CE
通讯作者：
Shaw CE
影响因子：
12.7
作者：
Marrone, Lara;Drexler, Hannes C. A.;Sterneckert, Jared
通讯作者：
Sterneckert, Jared
DOI：
10.1080/21678421.2020.1733021
发表时间：
2020-02-28
影响因子：
2.8
作者：
Flies, C. M.;Veldink, J. H.
通讯作者：
Veldink, J. H.
影响因子：
14.9
作者：
Humphrey, Jack;Birsa, Nicol;Fratta, Pietro
通讯作者：
Fratta, Pietro