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Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia
Published on: September 12, 2020
Integrative Identification of Candidate Protein Targets and Compounds for Dystonia Using Mendelian Randomization,
Lin Chen1, Ming-Juan Fang2, Nan Cheng1
1Anhui University of Chinese Medicine, Hefei 230061, China.
Background:
Dystonia is a severe neurological disorder with enigmatic pathogenesis. Current treatment options are limited in preventing the disease progression, underscoring the urgent need for new targeted therapeutic agents to develop more effective therapies.
Methods:
We performed a proteome-wide Mendelian randomization (MR) study and sensitivity analyses to evaluate the causal relationships between dystonia and proteins. GO and KEGG enrichment analysis of dystonia-associated proteins was conducted. Then, we built PPI network and identified the expression of hub-genes in specific brain neurons in single-cell sequencing data. Additionally, we performed drug enrichment analysis of hub-genes, and employed network pharmacology and molecular docking methods to identify potential drugs for dystonia.
Results:
Our study identified genetically predicted associations consistent with a potential causal effect between 51 proteins and risk of dystonia. GO and KEGG enrichment analyses revealed that these proteins are involved cellular response to transforming growth factor-β stimulation and cytokine-cytokine receptor interaction. Notably, the PPI network exhibited 21 community relationships within the regulatory network among the 51 dystonia-associated proteins identified. The single-cell RNA annotations for brain cluster specificity revealed Tumor necrosis factor (TNF) was highly expressed in microglia cells. Drug enrichment analysis identified five traditional Chinese medicine monomers (paeoniflorin, artesunate, ginsenoside Rh1, psoralen, and quercetin dihydrate) as candidates for molecular docking analysis. Among these, paeoniflorin-TNF, quercetin dihydrate-TNF, and artesunate-TNF exhibited the highest binding energy (-9.1 kcal/mol).
Conclusions:
Our molecular-docking analysis suggested that traditional Chinese medicine monomers including paeoniflorin, quercetin dihydrate, and artesunate may serve as promising candidates for future drug development.