Repurposing the Memory-promoting Meclofenoxate Hydrochloride as a Treatment for Parkinson's Disease through Integrative Multi-omics analysis

Parkinson's disease (PD) is a devastating neurodegenerative disorder with growing prevalence worldwide and, as yet, no effective treatment. Drug repurposing is invaluable for detecting novel PD therapeutics. Here, we compiled gene expression data from 1,231 healthy human brain samples and 357 samples across tissues, ethnicities, brain regions, Braak stages, and disease status. By integrating them with multiple-source genomic data, we found a PD-associated gene co-expression module, and its alignment with the CMAP database successfully identified drug candidates. Among these, meclofenoxate hydrochloride (MH) and sodium phenylbutyrate (SP) are indicated to be able to prevent mitochondria destruction, reduce lipid peroxidation and protect dopamine synthesis. MH was validated to prevent the neuronal death and synaptic damage, improve motor function, and reduce anhedonic and depressive-like behaviors of PD mice. The interaction of MH with a PD-related protein, sigma1 was confirmed experimentally. Thus, our findings support MH potentially ameliorating PD by interacting with sigma1. Overall design: To explore drug repurposing for Parkinson's Disease (PD), we developed a computational framework called iGOLD, which integrates multi-source genomic data with gene co-expression modules (Figure 1). This framework (available at https://github.com/fanc232CO/iGOLD_pipline) was used to identify gene co-expression modules affected by PD-related genes and SNPs. We evaluated the gene co-expression modules that were significantly enriched in PD-associated genes and SNPs through conservation analysis using seven gene expression datasets spanning various ethnicities, brain regions, tissues, Braak stages, and PD disease status. The highly conserved modules were then utilized for drug discovery. Subsequent experiments involved rotenone-induced primary neuronal cells and a mouse model to assess the efficacy of the identified drugs in promoting neuronal survival, enhancing hippocampal function, and modifying PD-related behaviors.