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pmid:41364313
A Novel Palmitoylation-Related Molecular Signature for Predicting and Therapeutically Targeting Alzheimer's Disease.
Xiuling Miao · Kaiyu Luo · Yinglei Li · Yang Zhou · Meng Wei · Ting Zhang · Yazhuo Hu · Heran Wang · Jianjun Jia
Molecular neurobiology · 2025 doi:10.1007/s12035-025-05574-1
Paper
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Experiment
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Data
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Analysis
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Execution
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Complete file
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Although palmitoylation has been implicated in AD, its specific mechanisms remain poorly defined. To investigate this, seven transcriptomic datasets were obtained from the GEO database. Differential expression and Gene Set Enrichment Analysis (GSEA) were performed across five training sets (GSE5281, GSE29378, GSE36980, GSE122063, and GSE132903). By intersecting differentially expressed genes (DEGs) with palmitoylation-related genes from GeneCards, 65 AD-associated palmitoylation-related genes (AD-PRGs) were identified. Functional enrichment analyses (KEGG and GO) were performed on these genes. Furthermore, seven key AD-PRGs (CALM1, VAMP2, SYT1, MET, BAG3, TJP1, NOTCH1) were prioritized using protein-protein interaction (PPI) networks and three machine learning algorithms (LASSO, SVM-RFE, and Random Forest). A diagnostic model constructed from these seven genes exhibited strong predictive performance, with AUC values of 0.834 in the training set and 0.907/0.865 in two external validation sets (GSE33000, GSE44770). Single-gene GSEA indicated associations with synaptic function and oxidative phosphorylation pathways. Protein docking analyses using GRAMM (Global RAnge Molecular Matching) and PISA (Proteins, Interfaces, Surfaces, and Assemblies) further suggested interactions between these key genes and Aβ/tau, supporting their involvement in AD pathogenesis. Additionally, regulatory network analysis identified 23 miRNAs, 33 transcription factors, and 14 potential therapeutic agents targeting these key genes. 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