Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.
Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.
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DOI：
10.1007/s00401-020-02183-1
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发表时间：
2020-11
影响因子：
12.7
通讯作者：
Hetz C
中科院分区：
文献类型：
--
作者：
García-Huerta P;Troncoso-Escudero P;Wu D;Thiruvalluvan A;Cisternas-Olmedo M;Henríquez DR;Plate L;Chana-Cuevas P;Saquel C;Thielen P;Longo KA;Geddes BJ;Lederkremer GZ;Sharma N;Shenkman M;Naphade S;Sardi SP;Spichiger C;Richter HG;Court FA;Tshilenge KT;Ellerby LM;Wiseman RL;Gonzalez-Billault C;Bergink S;Vidal RL;Hetz C
神经元蛋白质稳态受损是许多神经退行性疾病的显著特征，突出了内质网（ER）功能的改变。我们以前报道过，靶向转录因子XBP1，ER应激反应的关键介质，延缓疾病进展，减少各种神经退行性疾病模型中的蛋白质聚集。为了确定可能解释XBP1缺乏的神经保护作用的疾病修饰基因，我们对这些动物的大脑皮层和纹状体进行了基因表达谱分析，并发现胰岛素样生长因子2（Igf2）是主要的上调基因。在这里，我们研究了IGF2信号传导对亨廷顿病（HD）模型中蛋白质聚集的影响，作为概念验证。细胞培养研究表明，IGF2治疗减少了突变亨廷顿蛋白和多聚谷氨酰胺肽的细胞内聚集体的负荷。这些结果使用来自HD患者和脊髓小脑共济失调病例的诱导多能干细胞（iPSC）衍生的中等多棘神经元进行了验证。突变亨廷顿蛋白水平的降低与细胞内蛋白质半衰期的缩短有关。IGF2引发的异常蛋白聚集水平的降低与自噬和蛋白酶体途径的活性无关，这两种途径是突变亨廷顿蛋白清除的主要途径。相反，IGF2信号通过涉及肌动蛋白动力学变化的外泌体和微泡增强可溶性突变亨廷顿蛋白种类的分泌。在三种不同的动物模型中，使用基因治疗将IGF2施用到HD小鼠的大脑中导致突变亨廷顿蛋白水平的显著降低。此外，对HD患者的人类死后脑组织和血液样本的分析显示IGF2水平降低。这项研究确定IGF2作为HD中失调的相关因子，作为疾病修饰剂，缓冲异常蛋白质种类的积累。
Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington’s disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species.
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影响因子：
64.5
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
12.7
作者：
Duran-Aniotz, Claudia;Cornejo, Victor Hugo;Hetz, Claudio
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作者：
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Dynlacht, Brian David
影响因子：
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作者：
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