T32 clinical pharmacology fellow Mayo Clinic rochester, Minnesota, United States
Background: The protein tyrosine phosphatase, receptor type D (PTPRD) gene encodes a neuronal cell adhesion molecule which has been involved in multiple addiction related phenotypes, including alcohol use disorder (AUD). Our recent genome-wide association study (GWAS) showed that PTRRD SNPs were associated with AUD drug treatment (Acamprosate) response. However, molecular mechanism(s) for the involvement of PTPRD in AUD treatment response remain unknown. Methods: To study the molecular function of PTPRD in neurons, we performed RNA-seq assays using samples from human iPSC-derived neurons after PTPRD knock-down (KD) by antisense oligonucleotides (ASOs). Transcriptome-wide differentially expressed genes (DEGs) in neurons after PTPRD KD were identified, following by pathway enrichment analysis to gain understanding function of this gene in AUD treatment response Results: More than 90% KD of PTPRD was achieved in the iPSC-derived neurons. RNA-seq identified 439 DEGs (Log2FC >1, FDR < 0.05) after PTPRD KD. DEGs included SLITRK3 (Log2FC = -1.11, FDR = 1.25E-08), a known PTPRD binding partner. Pathway enrichment of those DEGs in the Gene Ontology (GO) Molecular Function identified a series of ion channels as well as neurotransmitter receptor activity pathways (adjusted p-value < 0.05). Those pathways were known to be related to the mechanism of action of Acamprosate which was used to treat AUD patients enrolled in our GWAS. Conclusion: Our study has generated transcriptome-wide data to help us understand the molecular function of PTPRD in human neurons. Future studies investigating PTPRD’s functional role in ion channel and neurotransmitter receptor activity might provide insight into the drug treatment response in AUD.
