Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis.
Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis.
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DOI：
10.1371/journal.pgen.1006805
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发表时间：
2017-05
期刊：
影响因子：
4.5
通讯作者：
Liebman SW
中科院分区：
文献类型：
--
作者：
Park SK;Hong JY;Arslan F;Kanneganti V;Patel B;Tietsort A;Tank EMH;Li X;Barmada SJ;Liebman SW
肌萎缩侧索硬化症(ALS)是一种毁灭性的神经退行性疾病，其特征是运动神经元选择性丢失，包涵体中经常含有RNA/DNA结合蛋白TDP-43。使用表现出TDP-43依赖毒性的ALS酵母模型，我们现在证明TDP-43的过度表达显著改变了细胞的形状，并减少了报告结构的泛素依赖的蛋白分解。此外，我们还表明，过量的HSP40伴侣蛋白SIS1降低了TDP-43‘S对细胞的毒性、细胞形态和蛋白降解的影响。这些作用的强度受到内源酵母蛋白[PIN+]的存在的影响。虽然SIS1的过表达改变了TDP-43的聚集模式，但我们没有检测到SIS1与TDP-43的物理联系，这表明可能对TDP-43的聚集有间接影响。此外，哺乳动物SIS1同源物DNAJB1的过表达减轻了TDP-43对原代啮齿动物皮质神经元的毒性，提示SIS1及其同源物在ALS中可能具有神经保护作用。许多神经退行性疾病与特定蛋白质的聚集有关。因此，我们对影响聚集的因素以及聚集的蛋白质如何与病理相关感兴趣。在这里，我们研究了一种名为TDP-43的蛋白质，它经常聚集在肌萎缩侧索硬化症(ALS)患者的神经元中。TDP-43聚集在一起，在酵母中表达时具有毒性，为ALS提供了一个有用的模型。值得注意的是，一种改变酵母中TDP-43毒性的蛋白质成功地预测了人类中一种新的ALS易感基因。我们现在报道一种新的TDP-43毒性修饰剂SIS1。我们发现，TDP-43在酵母中的表达抑制了受损蛋白质的降解，而Sis1的过表达则恢复了降解。这表明蛋白质降解和TDP-43毒性之间存在联系。此外，我们还表明，一种类似于SIS1的哺乳动物蛋白可以降低TDP-43对原代啮齿动物神经元的毒性。这表明哺乳动物类Sis1基因是ALS治疗的新靶点和可能的易感基因。
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons with inclusions frequently containing the RNA/DNA binding protein TDP-43. Using a yeast model of ALS exhibiting TDP-43 dependent toxicity, we now show that TDP-43 overexpression dramatically alters cell shape and reduces ubiquitin dependent proteolysis of a reporter construct. Furthermore, we show that an excess of the Hsp40 chaperone, Sis1, reduced TDP-43’s effect on toxicity, cell shape and proteolysis. The strength of these effects was influenced by the presence of the endogenous yeast prion, [PIN+]. Although overexpression of Sis1 altered the TDP-43 aggregation pattern, we did not detect physical association of Sis1 with TDP-43, suggesting the possibility of indirect effects on TDP-43 aggregation. Furthermore, overexpression of the mammalian Sis1 homologue, DNAJB1, relieves TDP-43 mediated toxicity in primary rodent cortical neurons, suggesting that Sis1 and its homologues may have neuroprotective effects in ALS. Many neurodegenerative diseases are associated with aggregation of specific proteins. Thus we are interested in factors that influence the aggregation and how the aggregated proteins are associated with pathology. Here, we study a protein called TDP-43 that is frequently aggregated in the neurons of patients with amyotrophic lateral sclerosis (ALS). TDP-43 aggregates and is toxic when expressed in yeast, providing a useful model for ALS. Remarkably, a protein that modified TDP-43 toxicity in yeast successfully predicted a new ALS susceptibility gene in humans. We now report a new modifier of TDP-43 toxicity, Sis1. We show that expression of TDP-43 in yeast inhibits degradation of damaged protein, while overexpression of Sis1 restores degradation. Thus suggests a link between protein degradation and TDP-43 toxicity. Furthermore we show that a mammalian protein similar to Sis1 reduces TDP-43 toxicity in primary rodent neurons. This identifies the mammalian Sis1-like gene as a new ALS therapeutic target and possible susceptibility gene.