Maintenance of protein homeostasis is critical for cellular viability and involves strict control of protein synthesis, folding and degradation over organismal lifespan. Conversely, excessive accumulation of intracytoplasmic, aggregate-prone proteins is a pathological hallmark of many age-related neurodegenerative disorders. Such misfolded proteins exert their effects via toxic gain-of-function mechanisms, thus processes involved in removal of the aggregate-prone proteins could impact disease progression and represent a rational therapeutic strategy in a range of neurodegenerative disorders.

Autophagy, which is often likened to a cellular waste disposal system, is a highly conserved pathway where cells engulf various cytoplasmic contents into double-membraned autophagosomes and traffic their contents to lysosomes for degradation and recycling. Rubinsztein lab has previously demonstrated that intracellular aggregate-prone proteins are autophagy substrates and that autophagy plays a key role in clearance of a number of proteins that have been associated with neurodegenerative diseases, such as Huntington’s disease and Parkinson’s disease.

The aim of my project is to explore a novel non-canonical autophagy pathway that was recently discovered in the lab as a potential therapeutic target in neurodegeneration. To achieve this, I will perform overexpression experiments in vitro and in vivo using zebrafish models of neurodegenerative disease, including tauopathy and Huntington’s disease models. I will then assess its effects on autophagic flux, clearance of intracytoplasmic protein aggregates as well as disease phenotype and progression. In the second part of my project, I will aim to identify pharmacological inducers of this pathway, with a goal to test the most promising compounds in induced pluripotent stem cell-derived cortical neurons and further animal models of disease.

Ultimately, our goal is to identify and characterise pharmacological autophagy stimulators that could have therapeutic potential in treatment of a range of neurodegenerative conditions.