Investigating the role of non-canonical PIKfyve/PI(5)P autophagy pathway on progression of neurodegenerative disease
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.