Nuclear autophagy; Functions in neuroprotection and tumor suppression

Autophagy is a cytoplasmic renovation mechanism that causes degradation and clearance of macromolecules such as pathogens, defective organelles and protein aggregates. PML bodies, on the other hand, represent distinct nuclear compartments that are known t o function in apoptosis, differentiation and DNA repair. This proposal is based on a collaborative effort between Anne Simonsen and Stig Ove Bøe's research groups whose main focus for many years have been to elucidate the mechanism of autophagy and PML bo dies, respectively. Based on our recent research, we propose a novel nucleo-cytoplasmic degradation pathway (herein referred to as nucleophagy), whereby PML bodies (together with their content) become transferred from the nucleus to the cytoplasm for subs equent clearance by autophagy. Furthermore, ongoing work in our laboratories implicate the involvement of nucleophagy in therapy-induced clearance of the oncogenic PML-RARA fusion protein that causes acute promyelocytic leukemia. Nucleophagy is the first cellular mechanism to be described that cause deposition and clearance of nuclear protein aggregates. In this project the mechanism of nuclear autophagy will be characterized further, and the role of this degradation pathway in the pathology of leukemia a s well as other diseases will be explored.