RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss.
RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss.
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DOI：
10.1016/j.celrep.2018.09.077
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发表时间：
2018-10-23
期刊：
影响因子：
8.8
通讯作者：
Kandel ER
中科院分区：
文献类型：
--
作者：
Kosmidis S;Polyzos A;Harvey L;Youssef M;Denny CA;Dranovsky A;Kandel ER
精确破译与年龄相关的记忆丧失的分子机制对于创造适当的治疗干预至关重要。我们之前已经证明，组蛋白结合蛋白RbAp48/Rbbp4是年龄相关性记忆丧失的分子决定因素。通过探索该蛋白如何调节海马回路的基因组景观，我们发现RbAp48控制BDNF和GPR158蛋白的表达，这两种蛋白都是小鼠海马骨钙素（OCN）信号传导的关键成分。我们发现，抑制海马区RbAp48会抑制OCN在认知中的有益功能，并导致辨别记忆的缺陷。反过来，OCN/GPR158信号的破坏导致RbAp48蛋白的下调，模仿在老年海马中观察到的区分记忆缺陷。我们还发现，OCN/GPR158通路的激活增加了老年齿状回中RbAp48的表达，并挽救了与年龄相关的记忆丧失。Kosmidis等人展示了骨钙素（一种由骨骼产生的激素）如何通过上调组蛋白结合蛋白RbAp48来改善与年龄相关的记忆丧失症状。
Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48/Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN’s beneficial functions in cognition and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein, mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss. Kosmidis et al. show how osteocalcin, a hormone produced by the bones, can ameliorate symptoms of age-related memory loss by upregulating the histone binding protein RbAp48.
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影响因子：
14.8
作者：
Beaudoin, Gerard M. J., III;Lee, Seung-Hye;Arikkath, Jyothi
通讯作者：
Arikkath, Jyothi
影响因子：
5.3
作者：
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通讯作者：
Thompson, RF
DOI：
10.1093/bioinformatics/btp472
发表时间：
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期刊：
Bioinformatics (Oxford, England)
影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
8
作者：
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通讯作者：
Brandner S