Pathways to decoding the clinical potential of stress response FOXO-interaction networks for Huntington's disease: of gene prioritization and context dependence

The FOXO family of transcription factors is central to the regulation of organismal longevity and cellular survival. Several studies have indicated that FOXO factors lie at the center of a complex network of upstream pathways, cofactors and downstream targets (FOXO-interaction networks), which may have developmental and post-developmental roles in the regulation of chronic-stress response in normal and diseased cells. Noticeably, FOXO factors are important for the regulation of proteotoxicity and neuron survival in several models of neurodegenerative disease, suggesting that FOXO-interaction networks may have therapeutic potential. However, the status of FOXO-interaction networks in neurodegenerative disease remains largely unknown. Systems modeling is anticipated to provide a comprehensive assessment of this question. In particular, interrogating the context-dependent variability of FOXO-interaction networks could predict the clinical potential of cellular-stress response genes and aging regulators for tackling brain and peripheral pathology in neurodegenerative disease. Using published transcriptomic data obtained from murine models of Huntington's disease (HD) and post-mortem brains, blood samples and induced-pluripotent-stem cells from HD carriers as a case example, this review briefly highlights how the biological status and clinical potential of FOXO-interaction networks for HD may be decoded by developing network and entropy based feature selection across heterogeneous datasets.