Ian Ganley's Research Group

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Molecular analysis of autophagy

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.

Ganley Lab Research

 

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).

Ganley Lab 2021: (L-R) Ian Ganley, Marianna Longo, Philippa Rosewell, Lea Wilhelm, Katharina Lorentzen, Francois Singh, Kevin Wu and Zhiyuan Li
Ganley Lab 2021: (L-R) Ian Ganley, Marianna Longo, Philippa Rosewell, Lea Wilhelm, Katharina Lorentzen, Francois Singh, Kevin Wu and Zhiyuan Li

People

Zhiyuan Li | Postdoctoral Researcher
Marianna Longo | PhD Student
Katharina Lorentzen | PhD Student
Philippa Rosewell | PhD Student
Francois Singh | Postdoctoral Researcher
Lea Wilhelm | Postdoctoral Researcher
Kevin Wu | Postdoctoral Researcher

Selected Publications

1   Singh F, Prescott AR, Rosewell P, Ball G, Reith AD, Ganley IG. (2021) Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice eLife 10 e67604
2   Zachari M, Longo M, Ganley IG (2020) Aberrant autophagosome formation occurs upon small molecule inhibition of ULK1 kinase activity Life Sci Alliance 3
3   Zhao, J-F., Rodger, C., Allen, G. F. G., Weidlich, S. & Ganley, I. G (2020) HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation Cell Stress
4   McWilliams, TG, Prescott, A, Villarejo-Zori, B, Ball, G, Boya, P & Ganley, (2019) A comparative map of macroautophagy and mitophagy in the vertebrate eye Autophagy 15 1296-1308
5   McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, Muqit MMK, Brooks SP, Ganley IG (2018) Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab 27 439-449
6   McWilliams, T. G., Prescott, A. R., Allen, G. F., Tamjar, J., Munson, M. J., Thomson, C., Muqit, M. M. and Ganley, I. (2016) mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol 214 333-345
7   Petherick, K. J., Conway, O. J., Mpamhanga, C., Osborne, S. A., Kamal, A., Saxty, B., Ganley, I. G. (2015) Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy J Biol Chem 290 11376-11383
8   Munson, M. J., Allen, G. F., Toth, R., Campbell, D. G., Lucocq, J. M., Ganley, I. G. (2015) mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival EMBO J 34 2272-2290
9   Allen, G. F., Toth, R., James, J., Ganley, I. G. (2013) Loss of iron triggers PINK1/Parkin-independent mitophagy EMBO Rep 14 1127-1135