GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation in CLN1 disease

Abstract

SummaryCLN1 disease, also called infantile neuronal ceroid lipofuscinosis, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). To identify depalmitoylation substrate of PPT1 is crucial to understand CLN1 disease. In this study, we found that PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and −179. Mutations of PPT1 or its GABAAR α1 subunit binding site result in enhanced inhibitory synaptic transmission, strengthened and oscillation but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient andGabra1em1mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in PPT1 induced diseases.