Autophagy, FOXO1 and proteostasis. Implications for human diseases

PhD ceremony: Ms. J. Yang, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Autophagy, FOXO1 and proteostasis. Implications for human diseases

Promotor(s): prof. H.H. Kamminga, prof. Wei-Guo Zhu

Faculty: Medical Sciences

Autophagy is a tightly regulated process in cells to remove dysfunctional or damaged cellular components before they become harmful. Deregulation of autophagy is implicated in diseases like cancer and neurodegeneration. In this thesis, we show that the longevity-associated transcription factor FOXO1 can increase autophagy. Intriguingly, this occurs independent from its transcriptional activity and reduced tumor development in mice, consistent with FOXO1 being a tumor suppressor and highlighting activating autophagy as a potential strategy for cancer treatment.

Boosting autophagy was also suggested to combat neurodegenerative diseases. We found that FOXO1 over-expression suppresses the toxic protein aggregation of proteins causative of Huntington’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis (ALS). Here, the FOXO1 transcription activity is required and its effect is unrelated to autophagy. We found that FOXO1 up-regulated both small heat shock proteins and the immunoproteasome, together boosting a proteolytic activity that seems to degrade un- or misfolded proteins species (just) prior to their aggregation. Finally, we found that knocking down hepatocystin, for which mutations have been shown to cause a rare form of polycystic liver disease (PCLD), leads to the increased autophagy. Here, the inhibition of autophagy (rather than activation) might be considered as a therapeutic invention for PCLD patients. Our observations highlight the importance of autophagy and protein quality control in health.