Principal Supervisor: Dr. Ioannis P. Nezis, School of Life Sciences
Co-supervisor: Dr Joanna Collingwood, School of Engineering
PhD project title: Molecular mechanisms of selective autophagy during inflammation and neurodegeneration
University of Registration: University of Warwick
Advances in modern medicine have led to a significant increase in human life expectancy. A consequence of this however, has been the increase of the frequency of ageing-related diseases. Recent studies have indicated that dysfunction in autophagy has been implicated in ageing-related diseases and especially in neurodegenerative diseases. Autophagy is an evolutionarily conserved catabolic process that involves the degradation of cytoplasmic material through the lysosomal pathway. It is a cellular response in nutrient starvation but it is also responsible for the removal of aggregated proteins, damaged organelles and developmental remodeling. Dysfunction in autophagy has been implicated in other diseases as well, like cancer, bacterial and viral infections (1). Although it was initially believed that autophagy occurs randomly inside the cell, during the last years there is growing evidence that sequestration and degradation of cytoplasmic material by autophagy can be selective through receptor and adaptor proteins (1).
Sustained increase in innate immune activity that has been associated with ageing. This is in contrast to the induction of an immune response by infection and its rapid termination when the pathogen is cleared. This heightened age-associated pro-inflammatory activity has been termed “inflammageing”. Other causes include the accumulation of tissue damage during the removal of senescent cells in various tissues and a defective autophagy response (2). It has been hypothesized that under certain conditions, heightened innate immunity may lead to age-associated brain neurodegeneration (3). Nevertheless, whether autophagy plays a role in the interplay between inflammation and neurodegeneration is still an open question.
To address the role of selective autophagy during inflammation and neurodegeneration, the fruit fly Drosophila melanogaster will be used as a genetically modifiable model organism. A yeast-two-hybrid screening performed in Nezis’ lab identified that the innate immune pathway components interact with the autophagic machinery. The aim of this project is to elucidate the role of these novel selective autophagy modulators in inflammation and neurodegeneration. Specifically, we will: 1) Confirm the interaction between autophagy and immune pathway related proteins biochemically and will identify their specific structural motif of that mediate these interactions. 2) We will examine whether these proteins are degraded by autophagy and how this affect the production of antimicrobial peptides in neuronal cells 3) We will define the physiological relevance of immunity related mutants during ageing, 4) We will examine the morphology of immunity related mutant brains using advanced synchrotron imaging. We expect to identify novel mechanisms of selective autophagy that regulate inflammation and neurodegeneration.
- He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 43:67-93.
- Salminen A., Kaarniranta K., Kauppinen A (2012). Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY) 4:166–175.
- Giunta B., Fernandez F., Nikolic W.V., Obregon D., Rrapo E., Town T., Tan J (2008). Inflammaging as a prodrome to Alzheimer’s disease. J. Neuroinflammation 5:51–66.
BBSRC Strategic Research Priority: Molecules, Cells and Systems
Techniques that will be undertaken during the project:
- Basic cell, molecular biology and biochemistry
- Drosophila genetics and cell biology
- Confocal microscopy
- Electron microscopy
- Synchrotron X-ray fluorescence microscopy
Contact: Dr. Ioannis P. Nezis, School of Life Sciences