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Understanding GABAA receptor protein folding and misfolding

了解 GABAA 受体蛋白折叠和错误折叠

基本信息

批准号：
10744869
负责人：
Tingwei Mu
金额：
$ 52.64万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744869
关键词：
ATF6 gene Address Anticonvulsants Autophagocytosis Binding Biogenesis Biological Assay Calnexin Cell membrane Cellular Assay Central Nervous System Clinical Complex Data Defect Degradation Pathway Development Disease model Electrophysiology (science)Endoplasmic Reticulum Epilepsy Equilibrium Family member Fluorescence Funding Genetic Heat-Shock Proteins 70 Human Image Induced pluripotent stem cell derived neurons Integral Membrane Protein Ion Channel Lysosomes Membrane Molecular Molecular Chaperones Pathogenicity Pathway interactions Patients Pharmacotherapy Polysaccharides Productivity Proteins Proteomics Publications RIPK1 gene Resistance Surface Ubiquitination Variant experimental study gamma-Aminobutyric Acid induced pluripotent stem cell loss of function multicatalytic endopeptidase complex novel strategies novel therapeutic intervention patch clamp pharmacologic protein degradation protein folding protein misfolding proteostasis receptor response small molecule trafficking zinc-binding protein

项目摘要

Project Description Loss of function of gamma-aminobutyric acid type A (GABAA) receptors is one prominent cause of genetic epilepsies since they are the primary inhibitory ion channels to maintain the excitation-inhibition balance in the mammalian central nervous system. Currently, hundreds of clinical variants have been identified in GABAA receptor subunits, causing their functional defects. Despite the development of numerous anti-seizure drugs, about one-third of epilepsy patients are resistant to current drug treatment, and many of them have genetic causes. Therefore, there is an urgent need to understand the molecular mechanism for the loss of function of pathogenic GABAA receptors as well as to develop a new therapeutic strategy to correct their function. It has been recognized that reduced surface trafficking of GABAA receptor variants is one major molecular mechanism for their loss of function. To reach the plasma membrane to carry out their function, GABAA receptor subunits need to fold and assemble into pentameric receptors in the endoplasmic reticulum (ER). Many epilepsy-causing GABAA receptor variants predispose them to protein misfolding in the ER and thus excessive protein degradation. Recently, we showed that we can correct the function of such variants by restoring their trafficking to the plasma membrane. Therefore, the overall objective of this proposal is to understand how cellular degradation pathways remove misfolding-prone GABAA receptor variants; furthermore, we hypothesize that we can correct the folding of these pathogenic variants to enhance their surface trafficking and thus function, as a novel strategy to treat genetic epilepsies. Here, in Specific Aim 1, we will characterize the cellular degradation pathways that remove misfolding-prone GABAA receptor clinical variants. In Specific Aim 2, we will elucidate a coordinated folding pathway that directs the protein folding of GABAA receptors in the ER. In Specific Aim 3, we will use small molecules to correct the folding and thus function of misfolding-prone GABAA receptor clinical variants.

项目描述 γ-氨基丁酸A型（GABAA）受体的功能丧失是导致糖尿病的一个主要原因。遗传性癫痫，因为它们是维持兴奋-抑制的主要抑制性离子通道哺乳动物中枢神经系统的平衡。目前，已经有数百种临床变异体，在GABAA受体亚基中鉴定，导致其功能缺陷。尽管开发了在众多的抗癫痫药物中，约三分之一的癫痫患者对目前的药物有抗药性治疗，其中许多都有遗传原因。因此，迫切需要了解致病性GABAA受体功能丧失的分子机制以及发展一种新的治疗策略来纠正它们的功能。人们已经认识到， GABAA受体变体的运输是其功能丧失的一种主要分子机制。到到达质膜以执行其功能，GABAA受体亚单位需要折叠，在内质网（ER）中组装成五聚体受体。许多引起癫痫的GABA 受体变体使它们易于在ER中发生蛋白质错误折叠，降解最近，我们表明，我们可以通过恢复这些变体的功能来纠正它们的功能。运输到质膜。因此，本提案的总体目标是了解细胞降解途径如何去除容易错误折叠的GABAA受体变体;此外，我们假设我们可以纠正这些致病变异体的折叠，贩运，从而发挥作用，作为一种新的战略，以治疗遗传性癫痫。在具体目标1中，将表征去除错误折叠倾向GABAA受体的细胞降解途径临床变异在具体目标2中，我们将阐明一个协调的折叠途径， ER中GABAA受体的蛋白质折叠。在具体目标3中，我们将使用小分子来纠正容易错误折叠的GABAA受体临床变体的折叠及其功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors.

DOI：
10.1371/journal.pone.0207948
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Fu YL;Han DY;Wang YJ;Di XJ;Yu HB;Mu TW
通讯作者：
Mu TW

Interactome Changes Quantified to Identify the ER Proteostasis Network to Fight Amyloid Diseases.

量化相互作用组的变化，以确定对抗淀粉样蛋白疾病的 ER 蛋白质稳态网络。

DOI：
10.1016/j.chembiol.2019.07.003
发表时间：
2019
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Wang,Ya-Juan;Mu,Ting-Wei
通讯作者：
Mu,Ting-Wei

Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants.

药理学伴侣可恢复癫痫相关 GABAA 受体变体的蛋白质稳态。

DOI：
10.1101/2023.04.18.537383
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Wang,Ya-Juan;Seibert,Hailey;Ahn,LucieY;Schaffer,AshleighE;Mu,Ting-Wei
通讯作者：
Mu,Ting-Wei

Anti-seizure mechanisms of midazolam and valproate at the β2(L51M) variant of the GABAA receptor.

咪达唑仑和丙戊酸在 GABAA 受体 β2(L51M) 变体上的抗癫痫机制。

DOI：
10.1016/j.neuropharm.2022.109295
发表时间：
2022
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Kuanyshbek,Alibek;Wang,Meng;Andersson,Åsa;Tuifua,Marie;Palmer,ElizabethE;Sachdev,RaniK;Mu,Ting-Wei;Vetter,Irina;Keramidas,Angelo
通讯作者：
Keramidas,Angelo