Fighting diseases through selective clearance of protein aggregates

The goal of this project is to unravel the molecular mechanisms underlying the regulation and execution of selective autophagy of aggregate-prone proteins (aggrephagy). Such knowledge might pave the way for development of targeted therapies for neurodegenerative disorders. We have previously found that the large protein ALFY is required for clearance of aggregates associated with a range of neurodegenerative disorders (Huntington’s and Parkinson’s disease and Amyotrophic Lateral Sclerosis) through its interaction with proteins and lipids in the autophagic membrane. Importantly, ALFY overexpression facilitates aggregate clearance in vivo, indicating that regulation of cellular ALFY levels or localization might be used therapeutically. ALFY is recruited from the nucleus to cytoplasmic aggregates and we have found this to be regulated by phosphorylation. We are currently also screening for other lipid-binding proteins involved in aggrephagy.

The PhD student will be involved in work aimed at elucidating the kinase and phosphatase involved in regulation of ALFY nuclear transport and their functional significance in ALFY cellular localization and role in aggregate clearance using cellular and animal models (mouse and zebrafish) of neurodegenerative disease. The PhD student may also be involved in functional characterization of candidates from the aggrephagy screen.