c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation.
c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation.
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C-Abl是一种非受体酪氨酸激酶，在阿尔茨海默病和帕金森病等多种神经退行性疾病的发病机制中起着重要作用。在这里，我们发现TDP-43是肌萎缩侧索硬化症(ALS)病理沉积的主要蛋白质之一，是c-Abl的新底物。C-Abl对TDP-43酪氨酸43的磷酸化导致SH-SY5Y细胞胞浆内TDP-43水平升高，G3BP1阳性应激颗粒的形成增多。C-Abl的激酶死亡突变体对TDP-43的胞质定位没有影响。TDP-43的模拟磷光突变体Y43E在原代皮质神经元中的表达积累了突起颗粒。此外，c-Abl对TDP-43酪氨酸43位的磷酸化促进了TDP-43的聚集，增加了原代皮质神经元的细胞死亡，但对c-Abl缺乏的原代皮质神经元没有影响。C-Abl是TDP43的激酶，为研究ALS的发病机制提供了新的思路。
Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl–deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS.
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影响因子：
3.5
作者：
Choksi, Darshana K.;Roy, Bidisha;Jackson, George R.
通讯作者：
Jackson, George R.
影响因子：
5.3
作者：
Derkinderen, P;Scales, TME;Anderton, BH
通讯作者：
Anderton, BH
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
3.5
作者：
Lee YB;Scotter EL;Lee DY;Troakes C;Mitchell J;Rogelj B;Gallo JM;Shaw CE
通讯作者：
Shaw CE
G3BP1促进应力诱导的RNA颗粒相互作用，以保留多腺苷酸化的mRNA。
DOI：
10.1083/jcb.201408092
发表时间：
2015-04-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Aulas A;Caron G;Gkogkas CG;Mohamed NV;Destroismaisons L;Sonenberg N;Leclerc N;Parker JA;Vande Velde C
通讯作者：
Vande Velde C