An Haiyan, Rabesahala de Meritens Camille, Buchman Vladimir L, Shelkovnikova Tatyana A
Medicines Discovery Institute, Cardiff University, Cardiff, CF10 3AT, UK.
Biomedicine Division, School of Biosciences, Cardiff University, Park Place, Cardiff, CF10 3AT, UK.
Mol Brain. 2020 May 13;13(1):77. doi: 10.1186/s13041-020-00618-0.
Mutations in the FUS gene cause a subset of ALS cases (ALS-FUS). The majority of FUS mutations are missense mutations affecting the nuclear localisation signal (NLS) of FUS. In addition, a number of frameshift mutations which result in complete NLS deletion have been described. Patients bearing frameshift mutations usually present with more aggressive disease, characterised by an early onset and rapid progression. Both missense mutations in the NLS coding sequence and complete loss of the NLS are known to result in cytoplasmic mislocalisation of FUS protein. However, in addition to the removal of FUS functional domains, frameshift mutations in most cases lead to the attachment of a "tail" of novel amino acids at the FUS C-terminus - a frameshift peptide. It is not clear whether these peptide tails would affect the properties of truncated FUS proteins. In the current study, we compared intracellular behaviour of disease-associated truncated FUS proteins with and without the corresponding frameshift peptides. We demonstrate that some of these peptides can affect subcellular distribution and/or increase aggregation capacity and stability of the truncated FUS protein. Our study suggests that frameshift peptides can alter the properties of truncated FUS variants which may modulate FUS pathogenicity and contribute to the variability of the disease course in ALS-FUS.
FUS基因的突变导致了一部分肌萎缩侧索硬化症病例（FUS型肌萎缩侧索硬化症）。大多数FUS突变是影响FUS核定位信号（NLS）的错义突变。此外，还描述了一些导致NLS完全缺失的移码突变。携带移码突变的患者通常表现出更具侵袭性的疾病，其特征为发病早且进展迅速。已知NLS编码序列中的错义突变和NLS的完全缺失都会导致FUS蛋白在细胞质中的错误定位。然而，除了去除FUS功能域之外，大多数情况下移码突变还会导致在FUS C末端连接一个新氨基酸的“尾巴”——一个移码肽。尚不清楚这些肽尾是否会影响截短的FUS蛋白的特性。在本研究中，我们比较了带有和不带有相应移码肽的疾病相关截短FUS蛋白的细胞内行为。我们证明，其中一些肽可以影响亚细胞分布和/或增加截短FUS蛋白的聚集能力及稳定性。我们的研究表明，移码肽可以改变截短FUS变体的特性，这可能会调节FUS的致病性，并导致FUS型肌萎缩侧索硬化症病程的变异性。
