FOXOs modulate proteasome activity in human-induced pluripotent stem cells of Huntington's disease and their derived neural cells.
FOXOs modulate proteasome activity in human-induced pluripotent stem cells of Huntington's disease and their derived neural cells.
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FOXO 调节人类诱导的亨廷顿病多能干细胞及其衍生神经细胞中的蛋白酶体活性。
DOI：
10.1093/hmg/ddx327
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发表时间：
2017
影响因子：
3.5
通讯作者：
Wang,Hongmin
中科院分区：
文献类型：
--
作者：
Liu,Yanying;Qiao,Fangfang;Leiferman,PatriciaC;Ross,Alan;Schlenker,EvelynH;Wang,Hongmin
虽然已经推测蛋白酶体功能障碍可能有助于亨廷顿病（HD）（一种破坏性神经退行性疾病）的发病机制，但蛋白酶体活性在HD影响的干细胞和体细胞中如何调节仍在很大程度上不清楚。为了更好地了解HD的发病机制，我们分析了蛋白酶体活性和FOXO转录因子在三个野生型（WT）和三个HD诱导的多能干细胞（iPSC）系中的表达。HD iPSC表现出升高的蛋白酶体活性和更高水平的FOXO 1和FOXO 4蛋白。敲低FOXO 4而非FOXO 1表达可降低蛋白酶体活性。在神经分化后，HD-iPSC衍生的神经祖细胞（NPC）表现出比其WT对应物更低水平的蛋白酶体活性和F0 XO表达。更重要的是，在HD NPC中FOXO 4而不是FOXO 1的过表达显著增强了蛋白酶体活性。当HD NPC进一步分化为DARPP 32阳性神经元时，这些HD神经元比WT神经元更容易死亡，并在氧化应激条件下形成Htt聚集体。与HD NPC类似，与WT-iPSC衍生的神经元相比，HD-iPSC衍生的神经元显示出降低的蛋白酶体活性和减少的F0 X 04表达。此外，HD iPSC具有比WT iPSC更低的AKT活性，而衍生自HD iPSC的神经元具有比它们的WT对应物更高的AKT活性。抑制AKT活性增加FOXO 4水平和蛋白酶体活性，表明AKT在调节FOXO水平中的潜在作用。这些数据表明，FOXO调节蛋白酶体活性，因此代表了HD的潜在有价值的治疗靶点。
Although it has been speculated that proteasome dysfunction may contribute to the pathogenesis of Huntington‘s disease (HD), a devastating neurodegenerative disorder, how proteasome activity is regulated in HD affected stem cells and somatic cells remains largely unclear. To better understand the pathogenesis of HD, we analyzed proteasome activity and the expression of FOXO transcription factors in three wild-type (WT) and three HD induced-pluripotent stem cell (iPSC) lines. HD iPSCs exhibited elevated proteasome activity and higher levels of FOXO1 and FOXO4 proteins. Knockdown of FOXO4 but not FOXO1 expression decreased proteasome activity. Following neural differentiation, the HD-iPSC-derived neural progenitor cells (NPCs) demonstrated lower levels of proteasome activity and FOXO expressions than their WT counterparts. More importantly, overexpression of FOXO4 but not FOXO1 in HD NPCs dramatically enhanced proteasome activity. When HD NPCs were further differentiated into DARPP32-positive neurons, these HD neurons were more susceptible to death than WT neurons and formed Htt aggregates under the condition of oxidative stress. Similar to HD NPCs, HD-iPSC-derived neurons showed reduced proteasome activity and diminished FOXO4 expression compared to WT-iPSC-derived neurons. Furthermore, HD iPSCs had lower AKT activities than WT iPSCs, whereas the neurons derived from HD iPSC had higher AKT activities than their WT counterparts. Inhibiting AKT activity increased both FOXO4 level and proteasome activity, indicating a potential role of AKT in regulating FOXO levels. These data suggest that FOXOs modulate proteasome activity, and thus represents a potentially valuable therapeutic target for HD.