Tong Jia, Gao Jingjing, Qi Yawei, Gao Ziyan, Wang Qianqian, Liu Yang, Yuan Tiangang, Ren Minglong, Yang Guixia, Li Zhaoyue, Li Jin, Sun Hongyuan, Zhao Xing, Leung Yeung-Yeung, Mu Yonghui, Xu Jiamin, Lu Chengbiao, Peng Shiyong, Ge Lihao
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China.
Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China.
Transl Psychiatry. 2024 Dec 18;14(1):488. doi: 10.1038/s41398-024-03206-1.
The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1 mice. Our study highlights the critical role of PPT1 in maintaining GABAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.
婴儿神经元蜡样脂褐质沉积症，也称为CLN1病，是一种由编码棕榈酰蛋白硫酯酶1（PPT1）的CLN1基因突变引起的致命性神经退行性疾病。确定PPT1的去棕榈酰化底物对于理解CLN1病至关重要。在本研究中，我们发现GABAR是抑制性神经传递所必需的关键突触蛋白，是PPT1的一种底物。PPT1在半胱氨酸-260处使GABARα1亚基去棕榈酰化，同时与半胱氨酸-165和-179结合。PPT1或其GABARα1亚基结合位点的突变增强了抑制性突触传递并增强了振荡功率，但破坏了CA1区的相位耦合，并损害了1至2月龄PPT1缺陷型和Gabra1小鼠的学习和记忆。我们的研究突出了PPT1在维持GABAR棕榈酰化稳态中的关键作用，并揭示了由PPT1突变诱导的CLN1病中一条以前未知的分子途径。
