Transcriptomics-Based Computational Drug Repurposing Strategy Identifies Therapeutic Candidates for Parkinson's Disease

Parkinson’s disease (PD) ranks as the second most prevalent age‐related neurodegenerativedisorder which associated with degeneration of dopaminergic neurons within the substantia nigra (SN)[۱]. Currently, no definitive disease-modifying treatment exists, and various treatments have beendeveloped to manage the symptoms of PD [۲]. Drug repurposing is a valuable alternative approach touncovering new indications of approved or investigational drugs that beyond of their original indication.RNA sequencing (RNA-seq) is one effective approach to finding the heterogeneous gene expressionsof diseases in response to specific drugs. Therefore, our study applied a computational drug repurposingpipeline to explore the candidate drugs by PD differential gene expression signatures derived from RNAsequencing data. The expression profiles of human post-mortem PD striatum under the accession codeGSE۲۰۵۴۵۰ were obtained from the GEO database (https://www.ncbi.nlm.nih.gov/geo/). This datasetincluded ۴۰ controls and ۳۵ PD samples. The differentially expressed genes (DEGs) between PD tissuesand normal tissues were obtained by using GEO۲R. Next, the Library of Integrated Network-basedSignatures (LINCS) database was used to identify potential candidate drugs which can reversed theexpression of DEGs. Then, through considerable literature review and drugbank(https://go.drugbank.com) studies, the top-ranked drugs with highest p-value were selected. This studyidentified ۵۶۲ genes with |log۲FC|>۱ and P-value <۰.۰۵ as DEGs: ۳۹۰ upregulated and ۱۷۲downregulated genes. In drug list, there are drugs for the treatment of cancer and non-cancer diseases,among which Mitoxantrone and Alvocidib can be mentioned. Mitoxantrone is initially developed aschemotherapeutic agent and then, it used for multiple sclerosis. Alvocidib is a cyclin-dependent kinase(CDK) inhibitor that exerts antitumor activity. In conclusion, this study proposed probably candidates(Mitoxantrone and Alvocidib ) for the treatment of PD progression that its can guide further repurposingstudies tailored to different stages of disease progression.

کلیدواژه ها:

RNA sequencing ، Parkinson’s disease ، Drug repurposing