Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons.
Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons.
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DOI：
10.1038/srep34904
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发表时间：
2016-10-10
影响因子：
4.6
通讯作者：
Inoue H
中科院分区：
文献类型：
--
作者：
Imamura K;Sahara N;Kanaan NM;Tsukita K;Kondo T;Kutoku Y;Ohsawa Y;Sunada Y;Kawakami K;Hotta A;Yawata S;Watanabe D;Hasegawa M;Trojanowski JQ;Lee VM;Suhara T;Higuchi M;Inoue H
编码tau（一种微管相关蛋白）的基因MAPT中的突变引起家族性神经退行性疾病的亚型，称为额颞叶变性tau蛋白病（FTLD-Tau），其表现为痴呆，特征在于大脑额叶和颞叶萎缩。虽然诱导多能干细胞（iPSC）技术促进了体外FTLD-Tau患者神经元细胞表型的研究，但仍不清楚FTLD-Tau患者神经元如何退化。在这里，我们通过神经生成素2诱导的来自FTLD-Tau患者iPSC的直接神经元分化建立了FTLD-Tau的神经元模型。我们发现FTLD-Tau神经元，无论是具有内含子MAPT突变还是具有外显子突变，都发生了错误折叠的tau的积累和细胞外释放，然后是神经元死亡，我们通过用CRISPR/Cas9校正内含子突变来证实。FTLD-Tau神经元表现出电刺激诱发的Ca 2+瞬变增强的调节异常。通过引入专门由设计药物（DREADD）激活的设计受体或通过用谷氨酸受体阻断剂治疗来化学发生学或药理学控制神经元活性相关的Ca 2+内流，可减弱错误折叠的tau蛋白积聚和神经元死亡。这些数据表明，神经元活动可以调节tau蛋白病中的神经变性。该FTLD-Tau模型提供了对tau蛋白病发病机制和潜在治疗途径的机制见解。
Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate. Here, we established neuronal models of FTLD-Tau by Neurogenin2-induced direct neuronal differentiation from FTLD-Tau patient iPSCs. We found that FTLD-Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death, which we confirmed by correction of the intronic mutation with CRISPR/Cas9. FTLD-Tau neurons showed dysregulation of the augmentation of Ca2+ transients evoked by electrical stimulation. Chemogenetic or pharmacological control of neuronal activity-relevant Ca2+ influx by the introduction of designer receptors exclusively activated by designer drugs (DREADDs) or by the treatment with glutamate receptor blockers attenuated misfolded tau accumulation and neuronal death. These data suggest that neuronal activity may regulate neurodegeneration in tauopathy. This FTLD-Tau model provides mechanistic insights into tauopathy pathogenesis and potential avenues for treatments.
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影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
3.5
作者：
Hasegawa, M;Smith, MJ;Goedert, M
通讯作者：
Goedert, M
影响因子：
14.5
作者：
McCarthy, Allan;Lonergan, Roisin;Lynch, Tim
通讯作者：
Lynch, Tim
影响因子：
4.6
作者：
Shoji E;Sakurai H;Nishino T;Nakahata T;Heike T;Awaya T;Fujii N;Manabe Y;Matsuo M;Sehara-Fujisawa A
通讯作者：
Sehara-Fujisawa A
影响因子：
16.2
作者：
Sanders DW;Kaufman SK;DeVos SL;Sharma AM;Mirbaha H;Li A;Barker SJ;Foley AC;Thorpe JR;Serpell LC;Miller TM;Grinberg LT;Seeley WW;Diamond MI
通讯作者：
Diamond MI