Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology.
Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology.
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DOI：
10.1007/s12035-023-03417-5
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发表时间：
2023-10
影响因子：
5.1
通讯作者：
Sachs, Jonathan N.
中科院分区：
文献类型：
--
作者：
Liao, Elly E.;Yang, Mu;Kochen, Noah Nathan;Vunnam, Nagamani;Braun, Anthony R.;Ferguson, David M.;Sachs, Jonathan N.
蛋白酶体降解固有的无序蛋白质，如tau，在衰老和神经退行性疾病中都是蛋白质稳定的关键组成部分。在本研究中，我们研究了MK886(MK)对蛋白酶体的激活作用。我们先前在细胞FRET实验中发现MK是一种能够调节tau齐聚并挽救P301L tau诱导的细胞毒性的先导化合物。我们首先使用20S蛋白酶体分析和细胞蛋白酶体tau-GFP裂解分析证实了MK对蛋白酶体的激活。然后，我们发现MK治疗可以显著挽救tau诱导的分化的SHSY5Y神经球中的轴突病理。由于这一引人注目的结果，我们设计了一系列七个MK类似物来确定蛋白酶体活性是否对结构排列敏感。使用蛋白酶体作为主要的MOA，我们检测了tau聚集，轴突生长，炎症和自噬分析，以确定MK的两个必需的取代基，这是化合物活性所必需的：(1)从MK中去除N-氯苯基既否定了蛋白酶体和自噬活性，并减少了轴突生长；(2)去除吲哚-5-异丙基显著促进了轴突生长和自噬活性，但降低了其抗炎能力。总体而言，我们的结果表明，蛋白酶体/自噬刺激和MK及其衍生物的抗炎特性相结合可以减少tau-tau的相互作用，帮助重新平衡功能失调的蛋白平衡。进一步开发MK以优化其蛋白酶体、自噬和抗炎靶点，可能会导致一种新的治疗方法，对衰老和神经退行性疾病有利。
Proteasomal degradation of intrinsically disordered proteins, such as tau, is a critical component of proteostasis in both aging and neurodegenerative diseases. In this study, we investigated proteasomal activation by MK886 (MK). We previously identified MK as a lead compound capable of modulating tau oligomerization in a cellular FRET assay and rescuing P301L tau-induced cytotoxicity. We first confirmed robust proteasomal activation by MK using 20S proteasomal assays and a cellular proteasomal tau-GFP cleavage assay. We then show that MK treatment can significantly rescue tau-induced neurite pathology in differentiated SHSY5Y neurospheres. Due to this compelling result, we designed a series of seven MK analogs to determine if proteasomal activity is sensitive to structural permutations. Using the proteasome as the primary MOA, we examined tau aggregation, neurite outgrowth, inflammation, and autophagy assays to identify two essential substituents of MK that are required for compound activity: (1) removal of the N-chlorobenzyl group from MK negated both proteasomal and autophagic activity and reduced neurite outgrowth; and (2) removal of the indole-5-isopropyl group significantly improved neurite outgrowth and autophagy activity but reduced its anti-inflammatory capacity. Overall, our results suggest that the combination of proteasomal/autophagic stimulation and anti-inflammatory properties of MK and its derivatives can decrease tau-tau interactions and help rebalance dysfunctional proteostasis. Further development of MK to optimize its proteasomal, autophagic, and anti-inflammatory targets may lead to a novel therapeutic that would be beneficial in aging and neurodegenerative diseases.
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影响因子：
4.6
作者：
Cheng C;Reis SA;Adams ET;Fass DM;Angus SP;Stuhlmiller TJ;Richardson J;Olafson H;Wang ET;Patnaik D;Beauchamp RL;Feldman DA;Silva MC;Sur M;Johnson GL;Ramesh V;Miller BL;Temple S;Kosik KS;Dickerson BC;Haggarty SJ
通讯作者：
Haggarty SJ
影响因子：
11.2
作者：
Chu, Jin;Pratico, Domenico
通讯作者：
Pratico, Domenico
影响因子：
6.8
作者：
Chu J;Lauretti E;Di Meco A;Praticò D
通讯作者：
Praticò D
影响因子：
64.8
作者：
HOFER, MM;BARDE, YA
通讯作者：
BARDE, YA
DOI：
10.1007/s12031-011-9502-x
发表时间：
2011-09
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
Guthrie CR;Kraemer BC
通讯作者：
Kraemer BC