Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.
Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.
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DOI：
10.18632/aging.203297
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发表时间：
2021-07-12
期刊：
影响因子：
--
通讯作者：
Reiman EM
中科院分区：
文献类型：
--
作者：
Dent P;Booth L;Roberts JL;Poklepovic A;Cridebring D;Reiman EM
Tau、淀粉样蛋白-β和TDP-43的异常表达和变性可导致细胞死亡，并且是诸如阿尔茨海默病（AD）的病理学的主要组成部分。AD神经元表现出形成自噬体和通过自噬降解蛋白质的能力降低。使用基因操作的结肠癌细胞，我们确定了直接抑制伴侣蛋白ATP酶活性或导致伴侣蛋白降解和内质网应激信号传导导致巨自噬的药物是否可以降低这些蛋白质的水平。抗病毒伴侣ATP酶抑制剂AR 12降低ATP酶活性和GRP 78、HSP 90和HSP 70以及Tau、Tau 301 L、APP、APP 692、APP 715、S 0 D1 G93 A和TDP-43的总表达。同时，它增加了ATG 13 S318和eIF 2A S51的磷酸化，并引起eIF 2A依赖性自噬体形成和自噬通量。Beclin 1或ATG 5的敲低阻止了伴侣蛋白、APP和Tau降解。来那替尼用于治疗HER 2+乳腺癌，通过巨自噬降低Tau和APP的伴侣蛋白水平和表达，来那替尼与AR 12相互作用，导致蛋白水平进一步降低。自噬调节蛋白ATG 16 L1表达为两种亚型，T300或A300：非洲人倾向于表达T300，欧洲人倾向于表达A300。当与同基因A300细胞相比时，我们观察到T300细胞中Tau的基础表达更高。ATG 16 L1亚型的表达并不改变A300细胞中HSP 90、HSP 70或HSP 27的基础水平，然而，GRP 78的基础水平降低。在A300细胞中，AR 12和Neratinib刺激ATG 13 S318和eIF 2A S51磷酸化和自噬通量的能力也降低。我们的数据支持在神经元细胞中进一步评价AR 12和来那替尼作为AD的再利用治疗。
Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.
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影响因子：
13.3
作者：
Chambraud, Beatrice;Daguinot, Corentin;Giustiniani, Julien
通讯作者：
Giustiniani, Julien
影响因子：
--
作者：
Booth L;Roberts JL;Poklepovic A;Avogadri-Connors F;Cutler RE;Lalani AS;Dent P
通讯作者：
Dent P
影响因子：
5.6
作者：
Booth L;Roberts JL;Rais R;Cutler RE Jr;Diala I;Lalani AS;Hancock JF;Poklepovic A;Dent P
通讯作者：
Dent P
影响因子：
5.6
作者：
Booth L;Roberts JL;Tavallai M;Nourbakhsh A;Chuckalovcak J;Carter J;Poklepovic A;Dent P
通讯作者：
Dent P
影响因子：
3.6
作者：
Booth, Laurence;Cazanave, Sophie C.;Dent, Paul
通讯作者：
Dent, Paul