TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.
TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.
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DOI：
10.1126/scitranslmed.abm5527
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发表时间：
2022-04-27
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Tau聚集体在细胞内的聚集是几种神经退行性疾病的标志。然而，tau的全球遗传减少在其他缺乏tau病理的大脑疾病模型中也是有益的，这表明非聚集tau的致病作用。在这里，有条件地消融tau在兴奋性但不是抑制性，神经元减少癫痫，癫痫中的突然意外死亡(SUDEP)，过度激活的磷酸肌醇3-激酶-AKT-雷帕霉素通路的哺乳动物靶标，脑过度生长(巨脑)，以及孤独症样行为的Drave综合征，一种严重的儿童期癫痫脑病的小鼠模型。此外，在出生后第10天开始使用降低tau的反义寡核苷酸治疗，在这个小鼠模型中也有类似的治疗效果。我们的发现表明，兴奋性神经元是一种关键的细胞类型，在这种细胞类型中，tau必须被减少，以抵消与Dravet综合征相关的大脑功能障碍，而且即使在出生后开始，整个大脑tau的减少也可能有类似的好处。兴奋性神经元中的tau消融和出生后脑tau的敲除减少了Dravet综合征模型中的癫痫、早期死亡和自闭症行为。
Intracellular accumulation of tau aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of tau is beneficial also in models of other brain disorders that lack such tau pathology, suggesting a pathogenic role of nonaggregated tau. Here, conditional ablation of tau in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy (SUDEP), overactivation of the phosphoinositide 3-kinase–AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a tau-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which tau has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral tau reduction could have similar benefits, even when initiated postnatally. Tau ablation in excitatory neurons and postnatal knockdown of brain tau reduce epilepsy, early death, and autism behaviors in a Dravet syndrome model.
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影响因子：
5.3
作者：
DeVos, Sarah L.;Goncharoff, Dustin K.;Miller, Timothy M.
通讯作者：
Miller, Timothy M.
影响因子：
4.7
作者：
Ewen, Joshua B.;Marvin, Alison R.;Lipkin, Paul H.
通讯作者：
Lipkin, Paul H.
影响因子：
2.2
作者：
Cooper, Monica S.;Mcintosh, Anne;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
5.6
作者：
Cheng AH;Fung SW;Hegazi S;Abdalla OHMH;Cheng HM
通讯作者：
Cheng HM
DOI：
10.1002/ajmg.c.31736
发表时间：
2019-08-23
影响因子：
3.1
作者：
Dobyns, William B.;Mirzaa, Ghayda M.
通讯作者：
Mirzaa, Ghayda M.