Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation.
Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation.
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DOI：
10.3390/biom10101367
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发表时间：
2020-09-25
期刊：
影响因子：
5.5
通讯作者：
Buchan JR
中科院分区：
文献类型：
--
作者：
Fernandes N;Nero L;Lyons SM;Ivanov P;Mittelmeier TM;Bolger TA;Buchan JR
应激颗粒（SGs）被假设为促进TAR DNA结合蛋白43（TDP-43）的胞质错误定位和聚集，这可能是肌萎缩侧索硬化症病理学的基础。然而，这一假设的许多数据是间接的。此外，P体（PB;相关mRNA-蛋白颗粒）是否影响TDP-43表型尚不清楚。在这里，我们确定了在酵母中诱导TDP-43表达导致SG样病灶的积累，在>90%的情况下，这些病灶成为TDP-43胞质病灶首次出现的部位。随后，TDP-43病灶与SG的相关性降低，与PB的相关性增加，尽管独立的TDP-43病灶也会累积。然而，耗尽或过表达酵母SG和PB蛋白揭示SG或PB组装与TDP-43焦点形成、毒性或蛋白质丰度之间没有一致的趋势。在人细胞中，用不同TDP-43抗体对内源性TDP-43进行免疫染色揭示了不同的定位和聚集行为。急性砷胁迫后，所有磷酸-TDP-43病灶与SG共定位。最后，在G3 BP 1/2ΔΔ细胞中，低剂量慢性砷胁迫后TDP-43胞质灶的形成受损，但未完全阻断。总的来说，我们的数据表明，SG和PB组装可能有助于TDP-43细胞质定位和聚集，但可能不是这些事件所必需的。
Stress granules (SGs) are hypothesized to facilitate TAR DNA-binding protein 43 (TDP-43) cytoplasmic mislocalization and aggregation, which may underly amyotrophic lateral sclerosis pathology. However, much data for this hypothesis is indirect. Additionally, whether P-bodies (PBs; related mRNA-protein granules) affect TDP-43 phenotypes is unclear. Here, we determine that induction of TDP-43 expression in yeast results in the accumulation of SG-like foci that in >90% of cases become the sites where TDP-43 cytoplasmic foci first appear. Later, TDP-43 foci associate less with SGs and more with PBs, though independent TDP-43 foci also accumulate. However, depleting or over-expressing yeast SG and PB proteins reveals no consistent trend between SG or PB assembly and TDP-43 foci formation, toxicity or protein abundance. In human cells, immunostaining endogenous TDP-43 with different TDP-43 antibodies reveals distinct localization and aggregation behaviors. Following acute arsenite stress, all phospho-TDP-43 foci colocalize with SGs. Finally, formation of TDP-43 cytoplasmic foci following low-dose chronic arsenite stress is impaired, but not completely blocked, in G3BP1/2ΔΔ cells. Collectively, our data suggest that SG and PB assembly may facilitate TDP-43 cytoplasmic localization and aggregation but are likely not essential for these events.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
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