PPT1 selectively depalmitoylates GAP43 to regulate neuronal excitability and cognitive function
to mediate its depalmitoylation, disruption of this interaction causes GAP43 hyperpalmitoylation that drove excessive dendritic arborization and aberrant growth cone expansion, enhanced glutamatergic transmission, and hippocampal network hyperexcitability, resulting in cognitive deficits without lysosomal storage pathology. Exogenous PPT1 reduced these morphological/synaptic abnormalities. Our findings establish the PPT1-GAP43 depalmitoylation pathway as essential for neuronal circuit homeostasis; its dysfunction contributes to neurodevelopmental disorders, identifying a potential therapeutic target for palmitoylation-related neurodevelopmental disorders.
Authors
- Yinming Liang (ORCID: https://orcid.org/0000-0001-9174-4037)
- Liaoxun Lu (ORCID: https://orcid.org/0000-0002-5342-2720)
- J L Liu
- Y F Liu
- Junyao Li (ORCID: https://orcid.org/0009-0002-3979-9983)
- W.T. Liu (ORCID: https://orcid.org/0000-0003-4885-1675)
- Paul de Chazot
- Wanliu Wu
- Huifang Yang
- Qianqian Wang
- Jia Tong (ORCID: https://orcid.org/0000-0003-1835-7385)
- Chengbiao Lu (ORCID: https://orcid.org/0000-0001-9074-4430)
- Ziyan Gao
Institutions
- Hunan University of Traditional Chinese Medicine (CN)
- Durham University (GB)
- Hunan Academy of Traditional Chinese Medicine (CN)
- Henan Medical University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-13
- DOI
- https://doi.org/10.1126/sciadv.aeb4675
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China