Why some proteins go astray in dementia: in conversation with Dr Sarah Mizielinska

When looking at a brain from an individual with dementia, a characteristic build-up of abnormal proteins is often seen alongside the substantial loss of neurons. These aggregations are of great interest to researchers, but could their location also offer clues as to the underlying causes of disease and, critically, opportunities for treatment? We caught up with Dr Sarah Mizielinska (UK DRI Group Leader at King’s) to find out more about her cutting-edge research into the mislocalisation of proteins, the importance of a multidisciplinary approach and her experiences starting a new family and lab group in academia.

Dr Mizielinska began her academic journey as a pharmacology undergraduate at the University of Bristol. Fascinated by the study of the brain but unsure of the next steps, she took a position as a lab technician, an experience she says encouraged her to embark upon a PhD, as well as preparing her for the challenge it presented.

“I really loved science and being in a lab doing research, but you don't get that much time for it during your undergraduate degree. So to go into a lab full time as a technician was a brilliant experience. I was very involved in the research and making decisions. I would highly recommend it and when I went into my PhD, I was more much more confident, like “I know exactly what the research world is. I know the challenges involved in it and I'm technically skilled in the lab.” It really was a major advantage and I think that it made the jump very easy.”

For her PhD, Dr Mizielinska explored how neurons respond and recover to cellular stress during stroke at the University of Dundee. It was there that her interest in neurological disease research was sparked, leading her to the lab of Prof Adrian Isaacs, now UK DRI Group Leader at UCL.

“I spent six years with Adrian and it was a really amazing experience that shaped my career. He has clear focus on the importance of disease relevance, which he shares and inspires in the people he mentors. I was taking studies all the way through from molecular biology, cellular work, animal studies, to human pathology. I was also fortunate to start working on the C9orf72 mutation in amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) from when it was first discovered, which was exciting and what I still research today.”

Amongst other findings Dr Mizielinska’s efforts in the Isaacs’ lab led to a significant Science publication in 2014, dissecting the molecular mechanism behind protein and RNA toxicity underlying ALS/FTD, caused by the most common C9orf72 mutation. This milestone provided Dr Mizielinska with the impetus to seek an independent research position, taking up a lectureship at King’s College London in the Department of Basic and Clinical Neuroscience led by Prof Chris Shaw at the time, and was one of the foundational Group Leaders when the UK DRI Centre was established by Prof Shaw at King’s.

Going nuclear

At UK DRI, Dr Mizielinska investigates the causes of ALS/FTD, with a particular focus on TDP-43, a protein with broad roles in the cell including gene regulation. TDP-43 is usually found in the nucleus, but in some neurodegenerative conditions it mislocalises to the cytoplasm where it aggregates . It is thought that the clinical symptoms seen in ALS/FTD may be a result of this phenomenon, as the presence of aggregated and mislocalised TDP-43 strongly correlates with degenerating brain regions in disease.

“My research question is trying to find out why this initial mislocalisation of TDP-43 happens. In rare cases of these diseases, there is a genetic mutation in TDP-43, but we still don't understand why that would lead to mislocalisation. We investigate why the transport between the nucleus and the cytoplasm becomes defective in disease. Not enough is known about this in a healthy cell, let alone what goes wrong in disease, so we’re having to study both.”

To investigate transport across the nuclear pore, a complex of proteins separating the nucleus and the cytoplasm, Dr Mizielinska’s lab takes different complementary approaches. Driven by the human pathology, they try to find characteristics of disease that they can recapitulate in cellular models and explain these by biophysical assessment of nuclear pore components in isolation. The team then take these models and use state-of-the-art technology to dissect the dynamics of movement across the nuclear pore.

“We’re using super resolution microscopy to track the movement of single molecules between the nucleus and cytoplasm, studying the dynamics of movement with resolution to within individual subdomains of the nuclear pore. This technology is more frequently used in cell biology using yeast models, but they have never yet been used to study disease in this context. The technology is allowing us to underpin the molecular mechanisms in a way that we couldn't before. We're also taking advantage of machine learning to overcome limitations of working with live cells.”

Carrying out this research at the single molecule level is a critical and unique aspect of the programme, explains Dr Mizielinska, as overall changes don’t indicate in which direction the issue with movement occurs and other approaches require use of reporters or blocking pathways that are all interdependent. Using her previous findings on toxicity resulting from the C9orf72 mutation in ALS/FTD, Dr Mizielinska has found significant dysfunction in the biophysical state of proteins that form the barrier within the nuclear pore, as well as the filtering component known as the nuclear basket.

Therapeutics have been developed to inhibit certain routes out of the cell’s nucleus, but unfortunately this does not seem to relate to the export pathway used by TDP-43. Dr Mizielinska explains that this is a good example of why fundamental discovery research is still required to learn more about basic molecular and cellular mechanisms, before developing effective treatments.

New beginnings

Dr Mizielinska’s recruitment to the UK DRI at King’s in 2017 marked the start of her independent research career and the launch of a new group – an exciting, but challenging experience as she explains.

“It's a very steep learning curve, especially with things that you don't normally associate with research such as admin, finances and people management. But I found the whole process really stimulating because you get to bring your own ideas to fruition, and then train other people, who contribute their ideas into the mix to find new solutions.”

The lab has grown since its inception with a core of five researchers, and an additional five positions shared with collaborating Group Leaders. Dr Mizielinska sees immense value in welcoming others to the team’s dynamic lab meetings, bringing with them diverse perspectives and expertise.

“I think a multidisciplinary approach is completely essential to study disease biology these days. Our group uses many techniques to fully explore our research question, and we even have someone with an engineering background applying their skills to biological systems. Having this variety of skillsets enriches all the projects that we undertake.”

Away from the workplace, Dr Mizielinska also started a new family, with her second child arriving just before the 2020 Covid-19 pandemic and associated lockdown. She reflects on the unique challenges of that experience, and ongoing obstacles faced by women in science.

“Starting a career as an academic whilst having a family is challenging, but of course very rewarding. I wouldn't change anything about it. You have to find a new balance because your time is now much more limited, but that is also a lesson in prioritisation and time management. It can help you focus on what's important because you don't have time to do everything.

As well as trying to catch up after the pandemic, there have also been ongoing challenges from Covid-19, which affect people with caring responsibilities in a compound way. Work is not only affected when you're ill or isolating, you’re also affected when that other person is ill or isolating too, or awaiting testing. And all of this is in addition to the normal exhaustion from raising children or other caring responsibilities.

There is also a large impact on early career researchers because research and outputs have been delayed which affects their next steps and fellowship schemes have also been paused and are still not as frequent as they were. And the effect is always going to be exacerbated for women, who have this added impact alongside the disruption from maternity leaves and caring responsibilities.”

We would like to thank Dr Sarah Mizielinska for taking the time to speak to us. You can find out more about her research on her UK DRI researcher profile.

Article published: 11 Feb 2022