Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability
Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability
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DOI：
10.1074/jbc.m109.031278
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发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Caccamo, Antonella;Majumder, Smita;Oddo, Salvatore
TDP-43是参与外显子跳跃和选择性剪接的核蛋白。最近，TDP-43已被确定为具有泛素阳性包涵体的额颞叶变性和肌萎缩侧索硬化症的病理标志蛋白。此外，TDP-43阳性包涵体存在于帕金森病、路易体痴呆和30%的阿尔茨海默病病例中。病理性TDP-43从细胞核重新分布到细胞质，并在细胞质中积累。TDP-43的一个类似于25-kDa的C-末端片段在受影响的脑区积累，表明它可能参与疾病的发病机制。在这里，我们表明，25 kDa的C-末端片段的过度表达足以导致内源性全长TDP-43在两个不同的细胞系中的错误定位和细胞质积累，从而概括了TDP-43蛋白病的关键生化特征。我们还发现TDP-43的错误定位与低分子量神经丝mRNA水平的降低有关。值得注意的是，我们表明自噬系统在TDP-43代谢中起作用。具体来说，我们发现自噬抑制增加TDP-43的C-末端片段的积累，而抑制mTOR（一种参与自噬调节的关键蛋白激酶）减少25-kDa C-末端片段积累并恢复TDP-43定位。我们的研究结果表明，自噬诱导可能是TDP-43蛋白病的有效治疗靶点。
TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An similar to 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.