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Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo.
Nature Neuroscience ( IF 25.0 ) Pub Date : 2017-11-20 , DOI: 10.1038/s41593-017-0022-z
Daniel J Apicco 1 , Peter E A Ash 1 , Brandon Maziuk 1 , Chelsey LeBlang 2 , Maria Medalla 2 , Ali Al Abdullatif 1 , Antonio Ferragud 1 , Emily Botelho 1 , Heather I Ballance 1 , Uma Dhawan 1 , Samantha Boudeau 1 , Anna Lourdes Cruz 1 , Daniel Kashy 1 , Aria Wong 1 , Lisa R Goldberg 1 , Neema Yazdani 1 , Cheng Zhang 3 , Choong Y Ung 3 , Yorghos Tripodis 4 , Nicholas M Kanaan 5 , Tsuneya Ikezu 1, 6 , Pietro Cottone 1 , John Leszyk 7 , Hu Li 3 , Jennifer Luebke 2 , Camron D Bryant 1 , Benjamin Wolozin 1, 6
Affiliation  

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

中文翻译:

减少 RNA 结合蛋白 TIA1 可防止体内 tau 介导的神经变性。

新兴研究表明 tau 在调节 RNA 结合蛋白 (RBP) 生物学中发挥作用。我们现在证明,在转基因 P301S Tau 小鼠中,体内减少 RBP T 细胞胞内抗原 1 (TIA1) 可防止神经退行性变并延长其存活时间。生化分级显示转基因 P301S Tau 小鼠中 tau 寡聚体和 RBP 的共富集和共定位。减少 TIA1 会减少与应激颗粒标记共定位的颗粒的数量和大小。减少 TIA1 也会抑制 tau 寡聚体的积累,但会增加神经原纤维缠结。尽管神经原纤维缠结增加,但 TIA1 的减少却增加了神经元的存活率,并挽救了行为缺陷和寿命。这些数据提供了体内证据,表明 TIA1 在介导毒性中发挥关键作用,并进一步表明 RBP 指导 tau 聚集途径以及由此产生的神经变性。我们提出了一个模型,其中翻译应激反应的功能障碍会导致 tau 介导的病理学。
更新日期:2017-11-21
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