FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells

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. Author summary The buildup of protein aggregates is deleterious to cellular function and can cause neurodegenerative disease. Healthy cells use a process known as autophagy to degrade aggregates and remove damaged proteins and organelles as needed. This process is particularly important in stem cells, which must clear damaged cellular material to prevent its inheritance down the lineage. The mechanisms that control overall levels of autophagy in stem cells are not well understood. Here, 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. We find that FOXO3 functions as a switch to induce autophagy in stem cells, and that its activity is required to restrain aggregate accumulation in these cells. This work is the first to elucidate a genomic program in neural stem cells that promotes aggregate clearance. Understanding how stem cells maintain protein quality control has important implications for using regenerative medicine to understand and treat age-related and degenerative diseases.