Project: Polyglutamine variants of huntington protein as a model cargo for Selective Autophagy

Unlike the non-specific uptake of cytoplasm associated with starvation-mediated autophagy, selective autophagy is a mechanism to identify and selectively clear the accumulation of cytosolic toxins by targeting them to the nascent autophagic membrane. Diseases associated with neurodegeneration, aging, infection and cardiac dysfunction often include selective autophagy of specific cargoes as either a causative or ameliorative event. These cargoes can include whole organisms such as S. Aureus (associated withpneumonia and endocarditis), organelles such as mitochondria (in Zellweger syndrome) and proteinaceous aggregates (as in Huntington's disease). How these selective cargoes are recognized, how they are targeted to the autophagic membrane and whether they play a functional role in the growth of the autophagosome are all unknown. To address these questions, we study the capture and turnover of polyglutamine associated protein aggregates, like those found in Huntington's disease. The advantages of this sort of model system are that the target is biochemically simple (a short, well-defined poly peptide) and therefore potentially tractable in both cell culture and in vitro reconstitution experiments. By capturing autophagosomes loaded with poly-gultamine tagged protein, we have been able to contribute to work from collaborators at Harvard (Dmitri Krainc (1)) and at Columbia (Ai Yamamoto (2)), that have begun to describe both how the cargo must be modified prior to autophagic uptake and what proteins may be involved in selective autophagy. In turn, we apply these model system to our characterization of our novel autophagy-associated proteins in order to delineate the pathways of starvation and selective macroautophagy.