Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants.
Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants.
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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
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mu,Ting-Wei
中科院分区：
文献类型：
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作者：
Wang,Ya-Juan;Seibert,Hailey;Ahn,LucieY;Schaffer,AshleighE;Mu,Ting-Wei
基因诊断的最新进展确定了编码GABAA受体的基因变异是遗传性癫痫的病因。在这里，我们选择了GABAA受体α1亚基中的8种疾病相关变体，导致轻度至重度的临床表型，并表明它们主要通过减少α1蛋白的折叠和表面运输而丧失功能。此外，我们寻求客户蛋白质特异性药理学伴侣，以恢复致病受体的功能。正变构调节剂（包括Hispidulin和TP 003）的应用增加了α1变体的功能性表面表达。作用机制研究表明，它们在HEK293 T细胞和人iPSC衍生的神经元中增强了GABAA变体的折叠、组装和运输，并减少了GABAA变体的降解，而不激活未折叠的蛋白质应答。由于这些化合物可以穿过血脑屏障，因此这种药物伴侣策略有望以GABA A受体特异性方式治疗遗传性癫痫。
Recent advances in genetic diagnosis identified variants in genes encoding GABAAreceptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAAreceptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding, assembly, and trafficking and reduce the degradation of GABAAvariants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAAreceptor-specific manner.