Deletion of VPS50 protein in mice brain impairs synaptic function and behavior.
Deletion of VPS50 protein in mice brain impairs synaptic function and behavior.
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小鼠大脑中 VPS50 蛋白的缺失会损害突触功能和行为。
DOI：
10.1101/2023.07.04.547745
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bustos,FernandoJ
中科院分区：
文献类型：
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作者：
Ahumada-Marchant,Constanza;Ancatén-Gonzalez,Carlos;Haensgen,Henny;Arancibia,Felipe;Brauer,Bastian;Droste,Rita;Horvitz,HRobert;Constantine-Paton,Martha;Arriagada,Gloria;Chávez,AndrésE;Bustos,FernandoJ
背景VPS 50蛋白在突触和致密核心囊泡酸化中发挥作用，VPS 50功能的紊乱可引起秀丽隐杆线虫的行为改变。VPS 50突变的患者表现出严重的发育迟缓和智力残疾，这些特征与自闭症谱系障碍（ASD）有关。将VPS 50突变与ASD联系起来的机制尚不清楚。ResultsTo研究VPS 50在哺乳动物脑功能和行为中的作用，我们使用CRISPR/Cas9系统在培养的小鼠皮层神经元和活小鼠中产生VPS 50的敲除。在培养的神经元中，KO的VPS 50不影响突触囊泡的数量，但确实引起V-ATP酶V1结构域泵的错误定位和受损的突触活性，可能是由于囊泡酸化和囊泡含量的缺陷。在小鼠中，马赛克KO的VPS 50在海马改变突触传递和可塑性，并产生强大的认知impairments.ConclusionsWe建议，VPS 50作为辅助蛋白的功能，以帮助招聘的V-ATP酶V1域的突触囊泡，并以这种方式起着至关重要的作用，在控制突触囊泡酸化。了解ASD相关突变中控制行为和突触功能的机制对于开发靶向干预措施至关重要，这可能为针对ASD和相关疾病的治疗策略开辟新途径。
BackgroundThe VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes inCaenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown.ResultsTo examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments.ConclusionsWe propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.