Our cells are constantly exposed to damaging stress from both external sources, such as UV rays, as well as internal sources, including free radicals produced by faulty mitochondria. Thankfully we have multiple ways to deal with this. One such protection mechanism is autophagy, an intracellular membrane-driven lysosomal degradation pathway. Autophagy protects cells by eliminating impaired and/or toxic components, which could lead to damage if left to persist. Because of this role, disruption of autophagy can have dire consequences and has been linked to many diseases including cancer, neurodegeneration and heart disease.
The goal of our research is to find ways to regulate this as yet poorly defined pathway so that autophagy can be used as a tool to treat disease. To do this, we need to identify physiological autophagy-inducing signalling pathways and determine how these signals trigger autophagosome formation. Towards this endeavour, we are focused on the ULK1 protein kinase complex, as this is critical for autophagy induction, yet how it does this is unclear. The ULK1 complex consists of multiple components and drives autophagy in both a kinase-dependent and independent manner. It is believed to act as a signalling node to convert diverse upstream signalling events, which include mTOR- and AMPK-dependent nutrient and energy sensing, into autophagosome formation. How these signals are integrated and the response they produce is a major focus of the lab.
Recently we developed mito-QC reporter models to detect mitophagy, the autophagy of mitochondria, disruption of which is implicated in Parkinson’s disease. We have uncovered multiple instances of physiological mitophagy, for example in dopaminergic neurons within the midbrain, and our objectives are to resolve these mechanisms, delineate the relevant signalling pathways and determine how they relate to development and disease. Our latest findings have shown that the most common mutation found in PD, the LRRK2 G2019S mutation, results in impaired mitophagy in vivo and this defect can be rescued by small molecule LRRK2 inhibitors. This holds promise for future therapeutics.
Diversity is key in all aspects of our work, ranging from the type of experiments we do, to the members of the lab. This enriches our science, productivity and inclusiveness. Whatever your background, we try to foster an open-minded approach to honestly answer important scientific questions about autophagy. Interested in joining us? Informal enquires can be made by e-mailing Ian Ganley (i.ganley@dundee.ac.uk).
