PDF(Pubmed)
Abstract：
TDP-43 forms aggregates in the neurons of patients with several neurodegenerative diseases. Human TDP-43 also aggregates and is toxic in yeast. Here, we used a yeast model to investigate (1) the nature of TDP-43 aggregates and (2) the mechanism of TDP-43 toxicity. Thioflavin T, which stains amyloid but not wild-type TDP-43 aggregates, also did not stain mutant TDP-43 aggregates made from TDP-43 with intragenic mutations that increase or decrease its toxicity. However, 1,6-hexanediol, which dissolves liquid droplets, dissolved wild-type or mutant TDP-43 aggregates. To investigate the mechanism of TDP-43 toxicity, the effects of TDP-43 mutations on the autophagy of the GFP-ATG8 reporter were examined. Mutations in TDP-43 that enhance its toxicity, but not mutations that reduce its toxicity, caused a larger reduction in autophagy. TOROID formation, which enhances autophagy, was scored as GFP-TOR1 aggregation. TDP-43 inhibited TOROID formation. TORC1 bound to both toxic and non-toxic TDP-43, and to TDP-43, with reduced toxicity due to pbp1Δ. However, extragenic modifiers and TDP-43 mutants that reduced TDP-43 toxicity, but not TDP-43 mutants that enhanced toxicity, restored TOROID formation. This is consistent with the hypothesis that TDP-43 is toxic in yeast because it reduces TOROID formation, causing the inhibition of autophagy. Whether TDP-43 exerts a similar effect in higher cells remains to be determined.
摘要：
TDP-43在患有几种神经退行性疾病的患者的神经元中形成聚集体。人TDP-43在酵母中也聚集并且是有毒的。这里,我们使用酵母模型来研究（1）TDP-43聚集体的性质和（2）TDP-43毒性的机制。硫黄素T,染色淀粉样蛋白而不是野生型TDP-43聚集体，也没有染色由TDP-43制成的突变TDP-43聚集体,其具有增加或降低其毒性的基因内突变。然而,1,6-己二醇,溶解液滴，溶解的野生型或突变型TDP-43聚集体。探讨TDP-43的毒性机制,研究了TDP-43突变对GFP-ATG8报道分子自噬的影响.TDP-43的突变增强了其毒性，但不是降低其毒性的突变，导致自噬更大幅度的减少。空隙形成,增强自噬，评分为GFP-TOR1聚集。TDP-43抑制TOROID形成。TORC1与有毒和无毒的TDP-43以及TDP-43结合，由于pbp1Δ而降低了毒性。然而,降低TDP-43毒性的外生修饰剂和TDP-43突变体，但不是增强毒性的TDP-43突变体，恢复了TOROID的形成。这与TDP-43在酵母中有毒的假设一致，因为它减少了TOROID的形成，抑制自噬。TDP-43是否在较高的细胞中发挥类似的作用仍有待确定。
