Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3.
Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3.
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DOI：
10.1016/j.stemcr.2021.09.013
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Freude KK
中科院分区：
文献类型：
--
作者：
Chandrasekaran A;Dittlau KS;Corsi GI;Haukedal H;Doncheva NT;Ramakrishna S;Ambardar S;Salcedo C;Schmidt SI;Zhang Y;Cirera S;Pihl M;Schmid B;Nielsen TT;Nielsen JE;Kolko M;Kobolák J;Dinnyés A;Hyttel P;Palakodeti D;Gorodkin J;Muddashetty RS;Meyer M;Aldana BI;Freude KK
额颞型痴呆(FTD3)是由带电多囊泡体蛋白2B(CHMP2B)的点突变引起的，它影响神经元中线粒体的超微结构和内溶酶体途径。为了分析CHMP2B突变表达对星形胶质细胞的特异性影响，我们从人诱导的多能干细胞(HiPSCs)中培养出星形胶质细胞，并在CHMP2B突变小鼠中证实了我们的发现。我们的数据提供了关于自噬缺陷如何导致线粒体动力学紊乱的机械性见解，其中糖酵解受损，活性氧增加，线粒体形态延长，表明FTD3星形胶质细胞线粒体融合增加。星形胶质细胞稳态的这种变化触发了星形胶质细胞的反应性表型和有毒细胞因子的释放增加，这些细胞因子在核因子kappab(NF-κB)途径的激活中积累，从而增加CHF、LCN2和C3的产生，导致神经变性。FTD3IPSC来源的星形胶质细胞显示自噬受损自噬受损影响线粒体更新，葡萄糖代谢低下和TCA循环FTD3星形胶质细胞通过增加C3，Lcn2，IL6和IL8反应性星形胶质细胞表型在体外和体内模型Chandrasekaran等人中都存在。展示有缺陷的自噬如何导致线粒体动力学紊乱，糖酵解受损，活性氧增加，以及导致神经退化的额颞型痴呆3型星形胶质细胞的线粒体形态拉长。
Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration. FTD3 iPSC-derived astrocytes display impaired autophagy Impaired autophagy affects mitochondria turnover, glucose hypometabolism and TCA cycle FTD3 astrocytes contribute to reactive gliosis by increased C3, LCN2, IL6, and IL8 Reactive astrocyte phenotypes are present in both in vitro and in vivo models Chandrasekaran et al. show the mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology in frontotemporal dementia type 3 astrocytes contributing to neurodegeneration.
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影响因子：
3.6
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通讯作者：
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影响因子：
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