Molecular and cellular mechanisms of selective autophagy and their relevance to ageing

Advances in modern medicine have led to a significant increase in human life expectancy. A consequence of this has been the increase of the frequency of ageing-related diseases. Recent studies have indicated that a breakdown of the autophagy system in cells is involved in the development of ageing-related diseases. Autophagy describes the essential process of cellular self-eating. Cells use autophagy to generate materials and energy when conditions become unfavourable. They also use this process to clear damaged cellular components. Initially it was thought that autophagy was a random process but there is growing evidence it is accomplished in a highly controlled, selective and specific manner. We will use the fruit fly, Drosophila melanogaster, as a genetically modifiable model organism to investigate autophagy during ageing and how it can contribute to the selective disposal of damaged and potentially toxic cellular material which may be the cause of ageing. These mechanisms are very similar between fruit flies and humans, so the results will have direct relevance to human health.
We aim to understand at molecular level how autophagy works and how specific proteins are identified to be degraded. We will then study how this process is affected during ageing and how it begins to break down and lead to age-related diseases developing.
This project will make a major contribution to our understanding of the fundamental mechanisms of selective autophagy and could potentially be used in applied research aimed towards developing new strategies to fight age-related diseases and to extend lifespan.

Ageing is associated with the lifelong, gradual accumulation of molecular and cellular damage and this has been observed in species ranging from yeast to humans. One of the phenotypic hallmarks of ageing cells is the intracellular accumulation of damaged proteins and organelles. Autophagy is an evolutionarily conserved lysosomal, self-degradation process. It is involved in protein and organelle degradation and plays an important role in both cellular and whole-organism homeostasis. Recent evidence indicates that autophagic activity declines with age and this gradual reduction of autophagy plays a causative role in the functional impairment of biological systems during ageing. Although it was initially believed that autophagy occurs randomly inside the cell, recently there has been growing evidence that sequestration and degradation of cytoplasmic material by autophagy can be selectively mediated through receptor and adaptor proteins. To understand cellular ageing, it is therefore important to identify the proteins required for recognition and targeting of the various autophagic cargos for degradation and to elucidate the molecular links between selective autophagy of damaged proteins and organelles and the regulation of ageing at the organismal level. We will use Drosophila melanogaster as a genetically modifiable model organism The first aim of this project is to understand the role of Ref(2)P (the Drosophila homologue of mammalian p62) during ageing. The second aim is to identify novel selective autophagy receptors and adaptors in Drosophila and examine their role during ageing. We will use a multidisciplinary approach by combining genetic, biochemical, bioinformatics, imaging and behavioral analysis. Using this approach we expect to identify novel mechanisms via which selective autophagy regulates ageing, and to elucidate the molecular details of selective autophagy in the context of cell and tissue physiology.

Ageing-related diseases, such as neurodegeneration, heart disease and cancer, are increasing in an ageing population and placing an increasingly large burden on the healthcare system. An understanding of the basic bioscience underpinning the ageing process is therefore necessary to improving the health and quality of life in this ageing population. A key feature of ageing is the decline of the autophagic activity in cells. Autophagy is an evolutionarily conserved process whereby cells degrade their own cellular material. It is involved in protein and organelle degradation and plays an essential role in both cellular and whole-animal homeostasis. It was initially believed that autophagy occurs randomly inside the cell, but now there is growing evidence that sequestration and degradation of cytoplasmic material by autophagy is selectively mediated through receptor and adaptor proteins. Our proposal focuses on selective autophagy and aims to understand its role during ageing, addressing fundamental, and as yet unresolved, issues that will allow us to identify the cellular and molecular pathways involved in to ageing and potential new targets for therapeutic intervention.

We are using the fruit fly Drosophila melanogaster, as our experimental organism as the molecular pathways we are investigating are highly conserved and respond in the same way in Drospophila as they do in mammals. The molecular, cellular, and genetic events we investigate will therefore be of relevance to human health and ageing. Working with Drosophila we are therefore able to produce results of relevance to human ageing without the use of vertebrate models, in line with the aims of the RCUK 3Rs programme: replacement, reduction and refinement.

The beneficiaries from this proposal will be (i) the academic research community of cell and molecular biologists searching for a molecular basis for normal ageing and ageing-related diseases; (ii) Potential benefits in the long term are discoveries that will contribute to therapeutic strategies for improving healthy wellbeing in the ageing population. Additionally, as we identify proteins as candidates for therapeutic intervention, the market for an anti-ageing therapeutic or dietary supplement would be a considerable economic beneficiary(iii) This proposal has potential longer-term benefits for ageing individuals, carers, the social and healthcare systems and society in general.

Impact will also be generated at the level of local scientific infrastructure contributing to the development of Warwick University. Our project will contribute to this process by the following means. 1) It will enhance the infrastructure of the institute by the consolidation of a research facility for Drosophila research that will provide access to a short-lived genetically tractable model of ageing. 2) We will be working on scientific problems that are of common interest for research groups in the institute and this is likely to enhance interactions between the groups and to stimulate collaborations. 3) It will produce world-class basic research helping to boost the reputation of Warwick University. 4) The results of our research have a potential to be applied to human health and therefore may become an intellectual property and to attract venture capital.

One of the more immediate outcomes of the project will be the professional training of the postdoc employed for the role of PDRA. PDRA will have an opportunity to learn and improve a wide range of techniques in genetics, molecular and cell biology as well as in vivo techniques. This will equip him/her well for a career as a scientist in academia or in a private sector. The highly skilled PDRA that we produce will most certainly lead ultimately to wealth creation through the applications of this transferable skills base. The project will also provide scope for public engagement having impact on better understanding and appreciation of basic science among the local community.