Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2.
Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2.
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DOI：
10.7554/elife.59432
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发表时间：
2021-07-12
期刊：
影响因子：
7.7
通讯作者：
Cullen PJ
中科院分区：
文献类型：
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作者：
McMillan KJ;Banks PJ;Hellel FL;Carmichael RE;Clairfeuille T;Evans AJ;Heesom KJ;Lewis P;Collins BM;Bashir ZI;Henley JM;Wilkinson KA;Cullen PJ
内体相关的货物适配器分选Nexin-27(SNX27)通过将整合蛋白分选到突触表面，尤其是AMPA受体，与多种神经病理联系在一起。为了更广泛地了解SNX27相关的病理，我们在大鼠原代神经元中进行了蛋白质组学研究，以确定SNX27依赖的货物，并确定了与兴奋性毒性、癫痫、智能障碍和工作记忆缺陷有关的蛋白质。以突触黏附分子LRFN_2为研究对象，我们发现SNX27与LRFN_2结合并调节其内体分选。此外，LRFN2与AMPA受体结合，LRFN2的敲除导致表面AMPA受体表达减少，突触活性降低，并减弱海马长时程增强。总之，我们的研究提供了一个额外的机制，SNX27可以通过对LRFN2的分类间接控制AMPA受体介导的突触传递和可塑性，并提供了对SNX27和LRFN2在一系列神经条件下的扰动功能的分子洞察。
The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.