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Abstract
Maintenance of a healthy proteome is essential for cellular homeostasis and loss of proteostasis is associated with tissue dysfunction and neurodegenerative disease. The mechanisms that support proteostasis in healthy cells and how they become defective during aging or in disease states are not fully understood. Here, we investigate the transcriptional programs that are essential for neural stem and progenitor cell (NSPC) function and uncover a program of autophagy genes under the control of the transcription factor FOXO3. Using genomic approaches, we observe that FOXO3 directly binds a network of target genes in adult NSPCs that are involved in autophagy, and find that FOXO3 functionally regulates induction of autophagy in these cells. Interestingly, in the absence of FOXO activity, aggregates accumulate in NSPCs, and this effect is reversed by TOR (target of rapamycin) inhibition. Surprisingly, enhancing FOXO3 causes nucleation of protein aggregates, but does not increase their degradation. The work presented here identifies a genomic network under the direct control of a key transcriptional regulator of aging that is critical for maintaining a healthy mammalian stem cell pool to support lifelong neurogenesis.
Highlights
IntroductionMaintenance of a healthy proteome, is critical for cellular homeostasis throughout life
Cellular proteostasis, or maintenance of a healthy proteome, is critical for cellular homeostasis throughout life
We show that a transcriptional regulator, FOXO3, which is critical for supporting stem cell functionality, regulates a genomic network of autophagy genes in mouse neural stem and progenitor cells
Summary
Maintenance of a healthy proteome, is critical for cellular homeostasis throughout life. Age-related diseases of the brain in particular (e.g. Alzheimer’s disease, Fronto-temporal dementia, Parkinson’s disease) are associated with aggregate accumulation, and disruptions in basal proteostasis can cause neurodegeneration in mouse models [2, 3]. Macroautophagy, hereafter referred to as autophagy, is a conserved catabolic pathway that functions to deliver cellular components to the lysosome for degradation by acid hydrolases [5]. Fusion of the autophagosome with the acidic lysosome to form an autolysosome results in cargo degradation. This process requires a number of proteins comprising the autophagic machinery, which coordinately regulate each step of the pathway according to the needs of the cell. Dysregulation of autophagy in either direction is deleterious to basal cellular function and impairs the cell’s ability to adjust to changing environmental conditions
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