Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents

Abstract

Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by people with CRCI resemble those experienced by people with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of people who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer’s disease and Parkinson’s disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson’s disease and/or Alzheimer’s disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer’s disease, Parkinson’s disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.