FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders

Abstract

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NFκβ, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.