GABA A R-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation.

Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101562664 Publication Model: Electronic Cited Medium: Internet ISSN: 2158-3188 (Electronic) Linking ISSN: 21583188 NLM ISO Abbreviation: Transl Psychiatry Subsets: MEDLINE

Original Publication: New York, NY : Nature Pub. Group

Thiolester Hydrolases*/genetics ; Thiolester Hydrolases*/metabolism ; Synaptic Transmission*/physiology ; Homeostasis*/physiology ; Lipoylation* ; Receptors, GABA-A*/genetics ; Receptors, GABA-A*/metabolism; Animals ; Mice ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/metabolism ; Humans ; Mice, Knockout ; Mutation ; CA1 Region, Hippocampal/metabolism

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.
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The experiments did not involve tissues from humans. Animal use and procedures were performed according to the regulations and requirements of XXMU Animal Ethics Committee (No. XYLL2021053).
(© 2024. The Author(s).)

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81771517 National Natural Science Foundation of China (National Science Foundation of China)

EC 3.1.2.- (Thiolester Hydrolases)
EC 3.1.2.22 (palmitoyl-protein thioesterase)
0 (Receptors, GABA-A)

Date Created: 20241218 Date Completed: 20241218 Latest Revision: 20241218

20241219

10.1038/s41398-024-03206-1

39695089