The Retromer Supports AMPA Receptor Trafficking During LTP
The Retromer Supports AMPA Receptor Trafficking During LTP
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DOI：
10.1016/j.neuron.2017.03.020
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发表时间：
2017-04-05
期刊：
影响因子：
16.2
通讯作者：
Malenka, Robert
中科院分区：
文献类型：
--
作者：
Temkin, Paul;Morishita, Wade;Malenka, Robert
逆转聚体是一种在内体分选中发挥特殊作用的多亚基蛋白质复合体，其功能的变化与阿尔茨海默氏症和帕金森病有关，但人们对逆转聚体在成熟大脑中的作用知之甚少。通过体内敲除关键的逆转录成分VPS35，我们证明了这种内体分选复合体在成熟海马突触的NMDA受体依赖的LTP期间AMPA受体的运输中发挥了特定的作用。VPS35基因敲除对LTP的损伤与APP产生抗体的逆转录过程无关。最后，我们发现阿尔茨海默病和帕金森氏病相关的VPS35突变在支持这一途径方面存在惊人的差异。这些发现证明了逆转录在LTP中的关键作用，并为了解成熟大脑中逆转录功能障碍如何导致常见神经退行性疾病的症状提供了见解。
Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTPdue toVPS35 knockdownwasmechanistically independent of anyroleof the retromerin theproduction of Ab from APP. Finally, we find surprising differences between Alzheimer's-and Parkinson's-disease-linked VPS35 mutations in supporting this pathway. These findings demonstrate a key role for the retromer in LTP and provide insights into how retromer malfunction in the mature brain may contribute to symptoms of common neurodegenerative diseases.