The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology.
The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology.
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DOI：
10.1038/s41380-018-0253-8
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发表时间：
2018-10
影响因子：
11
通讯作者：
Okazawa H
中科院分区：
文献类型：
--
作者：
Tanaka H;Kondo K;Chen X;Homma H;Tagawa K;Kerever A;Aoki S;Saito T;Saido T;Muramatsu SI;Fujita K;Okazawa H
阿尔茨海默病（Alzheimer's disease，AD）的早期病理学引起了人们的广泛关注，因为旨在清除β-淀粉样蛋白（beta-amyloid，Aβ）聚集体的药物的临床试验未能恢复症状性AD患者的记忆和认知功能。在这里，我们发现丝氨酸/精氨酸重复基质2（SRRM 2）的Ser 1068磷酸化，这是在早期AD小鼠模型和死后终末期AD患者的大脑中观察到的，通过抑制与T复合体蛋白亚基α的相互作用来防止其核转位。神经元中的SRRM 2缺陷会使多聚谷氨酰胺结合蛋白1（PQBP 1）（智力残疾（ID）的致病基因）不稳定，极大地影响突触相关基因的剪接模式，正如新生成的PQBP 1条件性敲除模型所证明的那样。PQBP 1和SRRM 2在人类AD患者和小鼠AD模型的皮层神经元中下调，并且AAV-PQBP 1载体在两种小鼠模型中恢复RNA剪接、突触表型和认知下降。最后，负责SRRM 2在Ser 1068处磷酸化的激酶被鉴定为ERK 1/2（MAPK 3/1）。这些结果共同揭示了AD病理学的一个新方面，其中影响RNA剪接和突触完整性的磷酸化信号先于细胞外Aβ聚集体的形成，并且可能与tau磷酸化平行进展。
Early-phase pathologies of Alzheimer’s disease (AD) are attracting much attention after clinical trials of drugs designed to remove beta-amyloid (Aβ) aggregates failed to recover memory and cognitive function in symptomatic AD patients. Here, we show that phosphorylation of serine/arginine repetitive matrix 2 (SRRM2) at Ser1068, which is observed in the brains of early phase AD mouse models and postmortem end-stage AD patients, prevents its nuclear translocation by inhibiting interaction with T-complex protein subunit α. SRRM2 deficiency in neurons destabilized polyglutamine binding protein 1 (PQBP1), a causative gene for intellectual disability (ID), greatly affecting the splicing patterns of synapse-related genes, as demonstrated in a newly generated PQBP1-conditional knockout model. PQBP1 and SRRM2 were downregulated in cortical neurons of human AD patients and mouse AD models, and the AAV-PQBP1 vector recovered RNA splicing, the synapse phenotype, and the cognitive decline in the two mouse models. Finally, the kinases responsible for the phosphorylation of SRRM2 at Ser1068 were identified as ERK1/2 (MAPK3/1). These results collectively reveal a new aspect of AD pathology in which a phosphorylation signal affecting RNA splicing and synapse integrity precedes the formation of extracellular Aβ aggregates and may progress in parallel with tau phosphorylation.
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影响因子：
4.6
作者：
Fujita K;Motoki K;Tagawa K;Chen X;Hama H;Nakajima K;Homma H;Tamura T;Watanabe H;Katsuno M;Matsumi C;Kajikawa M;Saito T;Saido T;Sobue G;Miyawaki A;Okazawa H
通讯作者：
Okazawa H
DOI：
10.1158/1078-0432.ccr-14-2124
发表时间：
2015-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Drilon A;Sylvester BE;Lovly CM;Borsu L;Reva B;Kris MG;Solit DB;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
4
作者：
Lubs, H.;Abidi, F. E.;Schwartz, C. E.
通讯作者：
Schwartz, C. E.
影响因子：
16.2
作者：
Okazawa, H;Rich, T;Kanazawa, I
通讯作者：
Kanazawa, I
影响因子：
14.8
作者：
Brewer, Gregory J.;Torricelli, John R.
通讯作者：
Torricelli, John R.