GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation

• Published in: Translational psychiatry 2024-12, Vol.14 (1), p.488-12
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/1; 14/19; 38/109; 631/378/340; 631/443; 64/110; 64/60; 692/699/476; 82/29; 82/51; 9/30; 9/74; Behavioral Sciences; Biological Psychology; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• 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 GABA A R, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABA A R α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABA A R 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 em1 mice. Our study highlights the critical role of PPT1 in maintaining GABA A R palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.