Investigating autophagic degradation of tau mediated by polyubiquitination Aberrant degradation and accumulation of tau in human brains is intimately connected to the development of Alzheimer’s disease (AD). Attentions are now directed to the cellular pathways responsible for the clearance of tau from neuronal cells, particularly through the autophagy-lysosome pathway. K63-linked polyubiquitination of tau is intimately involved in the early stage of autophagic degradation of tau. Compared to the better studied proteasomal degradation of tau, the recognition of tau by the autophagic machinery and the subsequent degradation by lysosome is poorly understood. Mechanistic details and in-depth biochemical characterization of the individual players and steps in this process are lacking. How the K63-linked polyubiquitination of tau mediates its autophagic degradation is largely unknown. Moreover, our understanding of tau deubiquitination and its role in regulating tau homeostasis is still very limited. We will address these unanswered questions using K63-polyUb-tau probes generated using a semi-synthetic approach to capture and identify cognate autophagic receptors and deubiquitinases that are responsible for modulation of the autophagic degradation of tau. Our findings will unveil new biology in this cellular process and provide potential new targets for pharmacological intervention of AD.