Mechanisms of autophagy regulation by the Fat/Hippo pathway

Neurodegenerative diseases are currently one of the top medical priorities. It is essential to understand the mechanisms through which the nerve cells (neurons) degenerate, to be able to design advanced therapies for protecting the cells. The process of autophagy, self-digestion, is of vital importance for human health in ageing and neurodgeneration. Autophagy is known to help neurons in keeping healthy through degradation of old and not functional cell components. We have discovered that new group of genes, acting in a pathway (the Fat/Hippo pathway), which is best known for its effects on cancer, is also essential for correct autophagy and neuronal health. We now wish to investigate the mechanism through which the Fat/Hippo pathway affects autophagy, so that new intelligent approaches can be designed for alleviating neurodegeneration by modulating the activity of this pathway.

Neurodegenerative diseases represent a significant human, societal and economic burden, and are a research priority in the biomedical sciences. Autophagy, a lysosomal catabolic process that disposes of unhealthy proteins and organelles, is currently considered essential for the development and progression of most neurodegenerative pathologies. Through advanced functional genomic studies in a Drosophila model for the neurodegenerative disease Dentatorubral-pallidoluysian atrophy, we have identified the tumour suppressor Fat and the growth control Hippo pathway as essential for neuronal homeostasis via autophagy. We have established that its effect in neuroprotection is not a secondary consequence of proliferation control. Rather, we report that the Fat/Hippo pathway critically affects autophagy and cell size in neurons. We now plan to study the mechanisms through which the Fat/Hippo pathway impacts on autophagy, in developing and adult post-mitotic neurons. In particular we will establish its intersection with the Tor pathway, known to be a key regulator of both autophagy and cell size, and thus a natural candidate for interacting with the Fat/Hippo pathway in this system.
Having pioneered the role of the Fat/Hippo pathway in neurodegeneration, we are ideally placed to perform these studies now, in a very supportive world-renown centre of excellence for neuroscience.
The proposed research will have an important biomedical impact, as it will establish the action of the Fat/Hippo pathway, an entirely new player in autophagy and neuronal homeostasis that can be potentially involved in several neurodegenerative conditions.