Lay Summary of our work

We are studying how  cells keep themselves tidy by tagging a small protein signal called Ubiquitin onto damaged or no longer needed proteins, leading to their destruction by the cells’ recycling centers.

Protein degradation in the brain: Relevance for Dementia.

Our research goal is to gain a much clearer understanding of the molecular changes that occur in the brain at the very earliest stages of dementia, perhaps even before symptoms can be easily detected.  Indeed it is now widely accepted that dementia is triggered 10-20 years before symptoms emerge which provides a huge challenge to the drug discovery process but at the same time provides a potentially very long therapeutic window to intervene and halt the disease.  We already know that dementia and other forms of neurodegeneration share a common characteristic, or pathological hallmark, which is the accumulation of toxic forms of aggregated protein in the brain.  The precise nature of the toxic proteins which aggregate in the various diseases may differ but the molecular principle is the same in that brain fails to get rid of them.  Therefore, we believe that the processes we are studying here are likely to be very relevant not only to Alzheimer’s Disease (AD) but also to fronto-temporal dementia, Lewy body disease and vascular forms of dementia so the potential benefits are widespread.  The questions we need to answer are, “why do toxic proteins accumulate in the brain in the first place” and “why are toxic proteins not cleared by the normal disposal routes which maintain a healthy brain”. We think that by studying and understanding these very early brain changes we will be able to identify targets for the development of new treatments for slowing the onset and/or progression of dementia. Even a modest delay in the onset of the disease would have a considerable benefit for the affected individual, an enormous impact globally in relation to the number of affected individuals at any given time and could offer a means of reducing the economic and social impact of dementia.

All cells within our body need to discard waste material such as damaged or no longer wanted proteins. This process, which conceptually is similar to the recycling of household waste, is key to ensuring that cells remain healthy and functional. This is particularly important in neuronal cells within the brain as failure to deal with waste leads to the accumulation of toxic proteins and aggregates in the form of extracellular plaques and intracellular tangles. A protein called ubiquitin functions as an identification tag labeling proteins that need to be discarded. Ubiquitin is added onto protein through a cascade of enzymatic reaction which is finely tuned and highly specific. We are studying how the enzymes which add and remove this small tag function and how they are regulated, in order to better understand why the degradation of mutant proteins and faulty organelles is reduced in aging brain cells. Our long-term goal is to manipulate these enzymes in order to boost the removal of mutant pathological proteins.

Protein degradation and cell growth: Relevance for cancer biology.

The question of why we age has intrigued mankind since the beginning of time. This question is even more relevant today, as the increase in human lifespan of the human race means that we spend more time in older age than ever before. The cell cycle, through its regulation of cell division, plays an important role in the ageing process. Dysregulation of the cell cycle is a hallmark of the ageing process and plays a crucial role in ageing-related disorders including cancer. At the organismal level, the division of one cell into two daughter cells is essential to maintain tissue renewal and repair, while at the cellular level it regulates cell growth and proliferation, cell death and cell ageing.

The molecular unravelling of the cell cycle by Sir Tim Hunt, Sir Paul Nurse and Leland Hartwell (Nobel Prize in Physiology or Medicine, 2001) has revealed unique insights into the machinery involved. The cell cycle consists of four phases, which correspond to: protein synthesis (G1); chromosome duplication (S); production of energy, growth of organelles (G2); and cell division (M or mitosis). To ensure that these phases occur sequentially and in an ordered manner, a number of lock gates are put in place. Cyclins are proteins which play critical roles in opening these gates and allowing the cell cycle to progress through to the next phase of the cell cycle. They achieve this by working together with enzymes known as Cyclin Dependent Kinases, to modify the activity of other proteins, which operate the key for these locks. Each phase of the cell cycle has its dedicated cyclin-CDK complex and, in order for the next phase to initiate, the previous cyclin-CDK needs to be deactivated which occurs through the removal of cyclins by protein degradation.

A few years after the discovery of cyclins, Aaron Ciechanover, Avram Hersko and Irwin Rose (Nobel Prize in Chemistry, 2004) identified a small protein called ubiquitin which tag proteins for degradation. During the cell cycle, ubiquitin tags cyclins for degradation thereby enabling the cycle to continue through to the next phase and to reach the last phase of the cell cycle, mitosis, where one cell becomes two. Ubiquitin forms chains on protein targets, which are like pearls on a string, with each pearl representing one ubiquitin molecule. There are 8 attachment sites on each ubiquitin, which can be used to assemble another molecule of ubiquitin in order to form a chain. These chains are formed by specific enzymes called E3 ubiquitin ligases or E3L, and the different types of ubiquitin chain formed have different shapes, properties and mediate specific cellular functions. We are studying the function of a novel  E3Ls involved in cell growth. This is are very important questions worth pursuing, as determining the molecular mechanisms driving cell growth and proliferation is key in order to better understand ageing-related disorders, in particular proliferative diseases such cancer.