Regulation of TDP-43 aggregation by phosphorylation andp62/SQSTM1
Regulation of TDP-43 aggregation by phosphorylation andp62/SQSTM1
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DOI：
10.1111/j.1471-4159.2010.07098.x
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发表时间：
2011-01-01
影响因子：
4.7
通讯作者：
Hu, Fenghua
中科院分区：
文献类型：
--
作者：
Brady, Owen A.;Meng, Peter;Hu, Fenghua
TAR DNA结合蛋白-43（TDP-43）蛋白质病与几种神经退行性疾病有关，如伴有泛素阳性包涵体的额颞叶变性和肌萎缩侧索硬化。磷酸化和泛素化的TDP-43 C-末端片段已被发现在额颞叶变性与泛素阳性包涵体和肌萎缩侧索硬化症患者的细胞质包涵体。然而，调节TDP-43聚集的因素和途径仍然不清楚。我们发现TDP-43的C-末端15 kDa片段足以诱导聚集，但聚集表型被额外的序列修饰。聚集伴随着丝氨酸残基409/410处的磷酸化。409/410突变为磷酸模拟天冬氨酸残基显著降低聚集。蛋白酶体或自噬的抑制显著增加TDP-43聚集。此外，TDP-43聚集体与自噬标志物和衔接蛋白p62/SQSTM 1共定位。p62/SQSTM 1的过表达以自噬和蛋白酶体依赖的方式减少TDP-43聚集。这些研究表明，TDP-43 C-末端片段的聚集受磷酸化事件以及自噬和蛋白酶体介导的降解途径的调节。
P>TAR DNA-binding protein-43 (TDP-43) proteinopathy has been linked to several neurodegenerative diseases, such as frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Phosphorylated and ubiquitinated TDP-43 C-terminal fragments have been found in cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis patients. However, the factors and pathways that regulate TDP-43 aggregation are still not clear. We found that the C-terminal 15 kDa fragment of TDP-43 is sufficient to induce aggregation but the aggregation phenotype is modified by additional sequences. Aggregation is accompanied by phosphorylation at serine residues 409/410. Mutation of 409/410 to phosphomimetic aspartic acid residues significantly reduces aggregation. Inhibition of either proteasome or autophagy dramatically increases TDP-43 aggregation. Furthermore, TDP-43 aggregates colocalize with markers of autophagy and the adaptor protein p62/SQSTM1. Over-expression of p62/SQSTM1 reduces TDP-43 aggregation in an autophagy and proteasome-dependent manner. These studies suggest that aggregation of TDP-43 C-terminal fragments is regulated by phosphorylation events and both the autophagy and proteasome-mediated degradation pathways.