The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.
The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.
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DOI：
10.1093/hmg/ddw232
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发表时间：
2016-09-15
影响因子：
3.5
通讯作者：
Carra S
中科院分区：
文献类型：
--
作者：
Crippa V;Cicardi ME;Ramesh N;Seguin SJ;Ganassi M;Bigi I;Diacci C;Zelotti E;Baratashvili M;Gregory JM;Dobson CM;Cereda C;Pandey UB;Poletti A;Carra S
TAR-DNA结合蛋白43（TDP-43）及其片段TDP-25和TDP-35的聚集发生在肌萎缩侧索硬化症（ALS）中。TDP-25和TDP-35作为TDP-43聚集的种子，改变其功能并发挥毒性。因此，抑制TDP-25和TDP-35聚集并促进其降解可保护细胞免受损伤。HSPB 8的上调是用于该目的的一种可能的方法，因为该分子伴侣促进了与TDP-43的片段相关的ALS的清除，并且在转基因ALS小鼠和人类患者的存活运动神经元中上调。我们报告说，HSPB 8在永生化运动神经元的过度表达减少了TDP-25和TDP-35的积累，并在果蝇中观察到对错误定位/截短TDP-43的保护作用。HSP 67 Bc是人HSPB 8的功能性直系同源物，过表达HSP 67 Bc可抑制由具有核定位信号突变的TDP-43变体（TDP-43-NLS）的细胞质积累引起的眼变性。TDP-43-NLS在视网膜细胞中的积累被HSP 67 Bc过表达抵消。根据这一发现，HSP 67 Bc的下调增加了眼变性，这与高分子量TDP-43物质和泛素化蛋白的积累一致。此外，我们报告了一种新的果蝇模型表达TDP-35，并表明，虽然TDP-43和TDP-25在苍蝇的眼睛表达导致轻度变性，TDP-35的表达导致严重的神经退行性变所揭示的脓毒症致死;后者的效果可以拯救HSP 67 Bc过表达。总的来说，我们的数据表明，在哺乳动物神经元细胞和苍蝇中，HSPB 8上调减轻TDP-43片段介导的毒性。
Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster. Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies.