Transcriptomic effects of propranolol and primidone converge on molecular pathways relevant to essential tremor.
Charles-Etienne CastonguayCalwing LiaoAnouar KhayachiYumin LiuMiranda MedeirosGabrielle HouleJay P RossPatrick A DionGuy A RouleauPublished in: NPJ genomic medicine (2022)
Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite this, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have previously been useful to identify disease related molecular targets. Notably, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive to two drugs: propranolol and primidone. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify convergent differentially expressed genes across treatments. Propranolol was found to affect the expression of genes previously associated with ET and other movement disorders such as TRAPPC11. Pathway enrichment analysis of these convergent drug-targeted genes identified multiple terms related to calcium signaling, endosomal sorting, axon guidance, and neuronal morphology. Furthermore, genes targeted by ET drugs were enriched within cell types having high expression of ET-related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.
Keyphrases
- genome wide
- single cell
- gene expression
- dna methylation
- deep brain stimulation
- poor prognosis
- parkinson disease
- cancer therapy
- rna seq
- bioinformatics analysis
- genome wide identification
- drug induced
- newly diagnosed
- end stage renal disease
- adverse drug
- cell therapy
- ejection fraction
- copy number
- genome wide analysis
- chronic kidney disease
- binding protein
- single molecule
- stem cells
- prognostic factors
- long non coding rna
- climate change
- brain injury
- mesenchymal stem cells
- patient reported outcomes
- optic nerve
- optical coherence tomography