Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1

Abstract

The global increase in lifespan noted not only in developed nations, but also in large developing countries parallels an observed increase in a significant number of non-communicable diseases, most notable neurodegenerative disorders. Neurodegenerative disorders present a number of challenges for treatment options that do not resolve disease progression. Furthermore, it is believed by the year 2030, the services required to treat cognitive disorders in the United States alone will exceed $2 trillion annually. Mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), the mechanistic target of rapamycin, and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system disease. These pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster, sometimes in conjunction with trophic factors, enhanced neuronal survival, reduction in toxic intracellular accumulations, and mitochondrial stability. Feedback mechanisms among these pathways also exist that can oversee reparative processes in the nervous system. However, mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1, mechanistic target of rapamycin, and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment, warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders.

Keywords: Alzheimer’s disease; FoxO; apoptosis; autophagy; erythropoietin; forkhead; mechanistic target of rapamycin; silent mating type information regulation 2 homolog 1.

Figure 1

Novel Core Pathways for mammalian forkhead transcription factors (FoxOs). FoxOs rely upon a network of pathways that oversee the onset and progression of neurodegenerative disease. Precise modulation of FoxOs through epigenetic and post-translation protein modifications is required to achieve the proper balance of FoxO activity for successful clinical care. FoxOs are controlled through phosphorylation, acetylation, and ubiquitylation that rely upon protein kinase B (Akt), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), and mTOR Complex 2 (mTORC2). Ultimately, pathways of autophagy and apoptosis are affected such that under some conditions increased autophagy activity can clear toxic intracellular accumulations and inhibition of apoptotic pathways can prevent cell death. These pathways also can work in conjunction with trophic factors such as erythropoietin (EPO) to increase neuronal survival and maintain mitochondrial stability.