Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment

Abstract

Neurocognitive impairment refers to a spectrum of disorders characterized by a decline in cognitive functions such as memory, attention, and problem-solving, which are often linked to structural or functional abnormalities in the brain. While its exact etiology remains elusive, genetic factors play a pivotal role in disease onset and progression. This study aimed to identify highly correlated gene clusters (modules) and key hub genes shared across neurocognition-impairing diseases, including Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma. Herein, the microarray datasets AD (GSE5281), HAND (GSE35864), glioma (GSE15824), and PD (GSE7621) were used to perform Weighted Gene Co-expression Network Analysis (WGCNA) to identify highly preserved modules across the studied brain diseases. Through gene set enrichment analysis, the shared modules were found to point towards processes including neuronal transcriptional dysregulation, neuroinflammation, protein aggregation, and mitochondrial dysfunction, hallmarks of many neurocognitive disorders. These modules were used in constructing protein-protein interaction networks to identify hub genes shared across the diseases of interest. These hub genes were found to play pivotal roles in processes including protein homeostasis, cell cycle regulation, energy metabolism, and signaling, all associated with brain and CNS diseases, and were explored for their drug repurposing experiments. Drug repurposing based on gene signatures highlighted drugs including Dorzolamide and Oxybuprocaine, which were found to modulate the expression of the hub genes in play and may have therapeutic implications in neurocognitive disorders. While both drugs have traditionally been used for other medical purposes, our study underscores the potential of a combined WGCNA and drug repurposing strategy for searching for new avenues in the simultaneous treatment of different diseases that have similarities in gene co-expression networks.