Maria is a first year PhD student supervised by Dr Sarah Marzi and Professor Paul Matthews. Her project is "Elucidation of epigenetic mechanisms involved in Parkinson’s Disease". Maria graduated with an integrated Master’s degree in Pharmacology from the University of Leeds in 2020.
March 2021
Dr Yu Ye is a UK DRI fellow and group leader, and a lecturer at Imperial College London. His work focuses on protein homeostasis in cell stress.
Maria: Could you start off with telling me about your career background?
Yu: I always had the fortune to be supported by great mentors. As an undergrad, I was influenced by my tutor and various structural biologists at Imperial to do a PhD at the MRC Laboratory of Molecular Biology in Cambridge. There, I joined David Komander’s lab as his first PhD student and studied the mechanisms of deubiquitinases. These are enzymes that remove molecular alterations, known as ubiquitin modifications, from proteins and seem to regulate a diverse range of pathways, from viral infection to inflammation and cancer. Following my PhD, I secured a Junior Research Fellowhip at Cambridge and a generous Sir Henry Wellcome Fellowship. My research focused on new methods in employing the proteasome system to reverse protein aggregation, mentored by Daniel Finley at Harvard and David Klenerman at Cambridge. I discovered a novel proteasome function, which broke down aggregates into smaller toxic species (oligomers). This demonstrates that all human cells have internal aggregate removal mechanisms.
Returning to Imperial, I am glad to land at our vibrant DRI Centre with fantastic new colleagues from whom I’ve learnt so much. I am grateful to Paul Matthews and my mentor Hugh Perry for inspirations for my research programme and for the guidance in assembling and consolidating my lab. The Imperial I returned is an open and vibrant University, especially when it comes to opportunities for people from diverse backgrounds. I feel proud to contribute to our Department’s missions and strengthening the College’s core values.
Maria: What does your research group at the UKDRI do?
Yu: We are looking into toxic protein aggregates like those seen in the brains of people with Alzheimer's or Parkinson's disease. We are particularly interested in proteasomes and their dysregulation in dementia. Proteasomes are biological recycling machines found in all cells and are responsible for selective degradation of proteins, including key factors that regulate important cellular processes. We hope to find a way to use proteasomes to remove the toxic aggregates, thereby preventing inflammation and neurodegeneration. Currently, we are working on two types of proteasomes: standard proteasomes, which exist in all of our cells at all times; as well as specific proteasomes, which exist in specialised cell types but could become upregulated in most cells upon challenges such as immune activation. We think standard proteasomes play important roles in regulating neuroinflammation, so our research aims to identify the roles, the activity and the functional overlap between the constitutive- and the standard proteasomes in brain cells with various disease backgrounds.
Maria: Are you looking at the immune cells of the brain, microglia, then?
Yu: We are looking at microglia, but there is also some data to suggest that specific proteasomes may be upregulated in neurons in certain brain disorders when challenged. This is very surprising for us, why would this be the case? Could this upregulation act as a signal for microglia to prune the neurons and result in their destruction? Could this potentially form a mechanism by which neuronal degeneration is accelerated? What roles do standard proteasomes play that are distinct to specific proteasomes? These are still very much open questions we wish to answer.
Maria: I suppose you work with cell lines, not animal models or human tissue?
Yu: We’re now interested in how standard proteasomes and specific proteasomes remove aggregates and the smaller toxic oligomers or, whether proteasomes might be inhibited by certain types of these oligomers. As we are mainly looking at the molecular and cellular stages of disease, we tend to work with cell lines derived from patient-donated samples.
Maria: That’s very interesting, what sort of techniques do you use to assess this?
Yu: In our lab, we combine a range of biochemical and gene-editing methods with advanced biophysical techniques. My background is in biophysical techniques and we currently have two dedicated super-resolution microscopes to study the modifications seen in aggregates inside cells. Our microscopes will be used to image intracellular processes of proteasomes, which can happen on a millisecond timescale. Our microscopes are built to capture these processes in both 2D and 3D.
Maria: Your papers seem quite rooted in chemistry. Could you explain a recent paper of yours and how it's related to neurodegeneration?
Yu: Yes. One thing that Liina (one of my PhD students) has been working on now is looking at how aggregates can be reversed by various combinations of proteasome assemblies. What we found in the Cliffe et al. 2019 paper, was that proteasomes unexpectedly break up fibrils into smaller entities, which is actually quite a toxic process to the cell. So, imagine you have a very stable fibril and it gets chopped up into many thousands of small pieces; the numbers increase, with the formation of small disaggregated entities, which enables them to better penetrate cell membranes. And this is actually adding to the toxicity. We then followed up this study showing that if you add a ubiquitin molecule to small aggregates, they can then be removed by the proteasome and properly degraded.
Maria: Have any recent breakthroughs in methods or technologies revolutionised the way aggregates are studied?
Yu: I think one thing that has revolutionised the field is cryo-EM. Michel Goedert, Sjors Scheres and their colleagues in Cambridge used cryo-EM to demonstrate that the fibrils associated with neurodegenerative diseases assume distinct structures. So, in other words, tau filaments from Alzheimer's disease are distinct in structure to the ones in Pick’s disease/frontotemporal dementia. The same distinction in filament structure is observed in multiple system atrophy and Parkinson’s disease for alpha-synuclein aggregates. Due to the resolution of cryo-EM, you could actually see that most of the aggregates were post translationally modified. My lab is also interested in how these modifications may prevent degradation/disassembly by proteasomes and accelerate aggregation.
Maria: When we’re talking about molecular details like protein aggregates in cells, it can be difficult to see how this translates directly into treatments for diseases. Could you explain how research into proteasomal activity will bring about medicines for dementia?
Yu: That's a very interesting question because ultimately what we want to achieve as dementia researchers is to enable an efficient route for translation of promising targets to therapeutic intervention. We know that the proteasome system is susceptible to drugs, indeed there is already a range of pre-approved drugs available for the proteasome. I also think that regulating standard proteasomes could be a novel secondary route to prevent neuroinflammation, and therefore retard the progress of dementia, perhaps in combination with other forms of treatments.
Maria: What are the biggest limitations that you face in your research at the moment?
Yu: Funding. I think this year the biggest limitation has been funding. Because of COVID, the planned budget of the entire DRI has suddenly become very strained. In my case, it has caused a lot of challenges as soon as I started my research programme and building my lab. The other thing is, I’m a trained experimental scientist so I like to be at the frontline and actively involved in every experiment of my three postdocs and two PhD students. I'm still in the transitional phase in learning to delegate to allow more time for administrational tasks!
Maria: Now a nice question. What motivates you to continue research?
Yu: I could go on for hours to answer that! Research for me is to discover something for the first time, something that no one else has done before. This is really what excites me! And this is what I use to motivate people in my lab. When we observe something under the microscope that people haven’t observed before, it’s a thrill! Especially the satisfaction you feel when you find out for the first time that your hypothesis is proven true. And I really hope that this will be the case for all our experiments. This is an important drive I seek when recruiting. Also, I am always thrilled when people come up to you at conferences or online to tell you they managed to reproduce your research. This is the best way to know that your research is actually being useful to other people, and that you're actually contributing to the advancement of science. I see science as an equaliser, because no matter what humble background we’ve come from we’re still allowed an equal chance in witnessing something novel and achieving something cool, because science is borderless and our research serves the entire humankind.
Maria: So, are you optimistic that we will have a breakthrough in Dementia Research?
Yu: Absolutely, 100%.
Maria: Why do you say that?
Yu: Well, I think we have already come a long way. If you think about 30 years back, people couldn’t differentiate between the pathology of many types of dementia. Although we still have a long way to go, dementia research is now gaining momentum.
I think to achieve our goals, interdisciplinary research is really what is critical here. For the ‘traditional’ diseases, e.g. bacterial and viral infection, we can perhaps drive more focused research to identify a monotherapy. Now for dementia and related disorders, we really require a multidisciplinary approach: first, to understand the whole picture of dementia including its causes, and second, to find a whole range of therapeutic interventions to target the various dysregulated biological aspects. And I really think that for complex neurodegenerative diseases, rather than a single target therapy, what we need is a range of therapies targeting different pathways to prevent the disease from progressing.
