Nucleation and dissolution mechanism underlying amyotrophic lateral sclerosis/frontotemporal lobar dementia-linked fused in sarcoma condensates.
Nucleation and dissolution mechanism underlying amyotrophic lateral sclerosis/frontotemporal lobar dementia-linked fused in sarcoma condensates.
复制标题
DOI：
10.1016/j.isci.2023.106537
复制
发表时间：
2023-04-21
期刊：
影响因子：
5.8
通讯作者：
Myong, Sua
中科院分区：
文献类型：
--
作者：
Djaja, Nathalie A.;Chang, Matthew T.;Morris, Freya R.;Morris, Vivian M.;Ganser, Laura R.;Myong, Sua
肉瘤融合蛋白 (FUS) 是一种核 RNA 结合蛋白。 FUS 突变导致 FUS 从细胞核错误定位到细胞质，并在神经退行性疾病中形成致病性聚集体，包括肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTLD)，但分子机制尚不清楚。利用突变和应激条件，我们可视化了细胞中的 FUS 定位和聚集体形成。我们使用单分子下拉 (SiMPull) 来量化细胞中野生型 (WT) 和突变型 FUS 的天然寡聚状态。我们证明，NLS 突变体表现出最高的寡聚化（> 3），其次是其他 FUS 突变体（> 2）和主要是单体的 WT FUS。引人注目的是，突变的 FUS 寡聚物非常稳定，能够抵抗高盐、己二醇、RNase 和 Karyopherin-β2 的处理，并且仅溶于 GdnHCl 和 SDS。我们认为突变体 FUS 寡聚单位的增加及其高稳定性可能有助于 ALS/FTLD 的发病机制。神经母细胞瘤细胞中的 FUS 野生型主要是细胞核中的单体 ALS/FTLD 连接的 FUS 突变体显示寡聚体增加，每簇高达 5-6 个单位 尽管在山梨醇胁迫下 FUS 斑点增加，但寡聚体保持不变 FUS 突变寡聚体非常稳定；他们坚持严酷的化学处理生物分子的特性；分子相互作用；生物物理学
Fused in sarcoma (FUS) is a nuclear RNA-binding protein. Mutations in FUS lead to the mislocalization of FUS from the nucleus to the cytosol and formation of pathogenic aggregates in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), yet with unknown molecular mechanisms. Using mutant and stress conditions, we visualized FUS localization and aggregate formation in cells. We used single-molecule pull-down (SiMPull) to quantify the native oligomerization states of wildtype (WT) and mutant FUS in cells. We demonstrate that the NLS mutants exhibited the highest oligomerization (>3) followed by other FUS mutants (>2) and WT FUS which is primarily monomeric. Strikingly, the mutant FUS oligomers are extremely stable and resistant to treatment by high salt, hexanediol, RNase, and Karyopherin-β2 and only soluble in GdnHCl and SDS. We propose that the increased oligomerization units of mutant FUS and their high stability may contribute to ALS/FTLD pathogenesis. FUS wildtype in neuroblastoma cells is primarily monomers in the nucleus ALS/FTLD-linked FUS mutants show increased oligomers up to 5–6 units per cluster Despite increased FUS puncta under sorbitol stress, oligomers remain unchanged FUS mutant oligomers are extremely stable; they persist harsh chemical treatments Properties of biomolecules; Molecular interaction; Biophysics
登录
查看更多内容
影响因子：
13.8
作者：
Ganser LR;Myong S
通讯作者：
Myong S
影响因子：
15.1
作者：
Baron DM;Kaushansky LJ;Ward CL;Sama RR;Chian RJ;Boggio KJ;Quaresma AJ;Nickerson JA;Bosco DA
通讯作者：
Bosco DA
影响因子：
5.5
作者：
Milicevic K;Rankovic B;Andjus PR;Bataveljic D;Milovanovic D
通讯作者：
Milovanovic D
影响因子：
2.3
作者：
Gitler, Aaron D.;Shorter, James
通讯作者：
Shorter, James
影响因子：
64.8
作者：
Li, Pilong;Banjade, Sudeep;Cheng, Hui-Chun;Kim, Soyeon;Chen, Baoyu;Guo, Liang;Llaguno, Marc;Hollingsworth, Javoris V.;King, David S.;Banani, Salman F.;Russo, Paul S.;Jiang, Qiu-Xing;Nixon, B. Tracy;Rosen, Michael K.
通讯作者：
Rosen, Michael K.