Molecular mechanisms of selective autophagy during inflammation and neurodegeneration

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

Global human population over the age of 60 will increase more than threefold (to nearly 2 billion individuals) during the first half of the twenty-first century, and that by 2050 it will exceed the size of the global population of young individuals (those individuals who are less than 15 years of age). For the first time in history, there are 11 million people aged 65 or over in the UK and also there are more pensioners than there are children under 16. Ageing population puts an enormous pressure on health care and pension system. Thus, understanding the biology of ageing is an urgently required task in order to ensure a viable and sustainable future for our human community. One of the phenotypic hallmarks of ageing cells is chronic, systemic inflammation in the absence of any apparent infection, and is a significant risk factor for mortality in the elderly and is linked to neurodegeneration. We have found that autophagy plays a role in the regulation of innate immunity. Autophagy, which means 'self-eating', is an essential process that involves the degradation of cytoplasmic material. Cells use autophagy to generate materials and energy when conditions become unfavourable. They also use this process to clear damaged cellular components or specific proteins in order to abolish their function when it is not needed in the cell. We will use the fruit fly Drosophila melanogaster as a genetically modifiable model organism to understand at the molecular level how selective autophagy regulates inflammation and neurodegeneration during ageing. These mechanisms are very similar between fruit flies and humans, so the results will have direct relevance to human health. Specifically, we will: 1) Identify novel autophagy related proteins interactors, 2) We will examine how these interactors affect the production of antimicrobial peptides and how this affects neurons, 3) We will define the physiological relevance of the mutated identified interactors during ageing.

Publications

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Tsapras P (2017) Caspase involvement in autophagy. in Cell death and differentiation

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Tsapras P (2019) Assays to Monitor Mitophagy in Drosophila. in Methods in molecular biology (Clifton, N.J.)

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1786919 Studentship BB/M01116X/1 03/10/2016 30/03/2021 Panagiotis Tsapras
 
Description As we age several cellular processes crucial for our healthy well-being start to progressively wane, leading to age-associated symptoms becoming more frequent, such as neurodegeneration. One such process is our immune response to invading pathogens. Normally, this defense is acute and transient in nature, responding to an invading pathogen and falling back to a basal state shortly after the initial threat has been cleared by the cell. Activation and de-activation of the pathway are tightly regulated as if left unchecked, the defense mechanisms primarily employed for neutralizing the pathogen can start negatively impacting other non-inflammatory related functions that are crucial for a cell's well-being. Chronic inflammation is defined as a constantly active immune response above basal levels in the absence of any external stimuli and is considered a characteristic hallmark of ageing. Elevated levels of inflammatory markers are common especially among the elderly population and as such the term "inflammageing" is used, in order to emphasize the contribution of chronic inflammation to the ageing process and the age-associated decline in health.

Autophagy is one of the cell's recycling pathways for removing accumulated intracellular debris and damaged organelles, that would otherwise cause damage if left uncleared. In doing so autophagy promotes the cell's viability in a healthy manner, and is primarily considered a survival pathway.

Our lab has previously shown that in the fruit fly (our choice of model organism to study aspects of the human condition in the whole organism level) autophagy is one of the factors that regulate activation of the immune-response pathway by selectively removing key components from its signalling cascade and degrade them, thus contributing to the switch-off the pathway when it is no longer needed. Atg8a is the key protein associated with autophagy, that sequesters other targets by interacting with them and thus removing them from their signalling cascades and re-routing them for degradation. We have found that Atg8a binds one of the downstream key effector proteins for the anti-inflammatory response in the fruit fly, and in doing so aids in the fine-tuning of the immune response. Currently, we have characterized that Atg8a also binds the apical upstream activator protein complex of this immune-signalling cascade. Furthermore, we are the first to demonstrate that a protein important for autophagy but previously unassociated with this immune-pathway, is also essential for its regulation at the same apical level. These results suggest that autophagy is heavily involved in the efficient regulation of this immune-signalling cascade. As of to-date, we are delineating the nature and role of these interactions at the apical activator level of the particular anti-inflammatory pathway, that collectively seem to recruit autophagy on-site. Consequently, keeping in line with our overarching context of extending healthspan well into old age, we are also studying how perturbations of these interactions can impact the effective regulation of inflammatory-signalling by autophagy in the fruit fly during ageing and age-associated neurodegeneration. All above proteins have their evolutionary conserved counterparts in humans, that take part in the same cellular processes.
Exploitation Route Potential for pharmaceutical application in the developing of more target-specific drugs to restore proper regulation of the anti-iflammatory pathway and tackle certain symptoms of age-associated disorders.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology