FLAG Researcher Spotlight: Dr Kyrah Thumbadoo

Dr Kyrah Thumbadoo

“I didn’t know how to bridge the gap between my two interests until I entered research, where it’s possible to focus on specific scientific questions that have a hand in helping patient outcomes”

Hi Kyrah, can you tell us a little about yourself and your research interests? What is your title and your institution?

Hello, I am Kyrah Thumbadoo, a Research Fellow at the University of Auckland. I am originally from South Africa and moved to New Zealand when I was ten. I’ve always loved science growing up, and knew I wanted to work in health and help people. Because of this, I did a Bachelor of Health Sciences and Science conjoint at the University of Auckland, majoring in Pharmacology and Health Sciences. These two degrees are quite opposite ends of the spectrum – one investigating cellular drug responses and the other examining population health, which gave me a great foundation of health and health research in Aotearoa. Initially, I didn’t know how to bridge the gap between my two interests until I entered research, where it’s possible to focus on specific scientific questions that have a hand in helping patient outcomes on the macro level.

I did my honours and PhD projects on motor neuron disease (MND) in the Motor Neuron Disease Research Lab led by Associate Professor Emma Scotter at the University of Auckland. Interestingly, New Zealand has some of the world’s highest rates of MND, so work contributing to our understanding of MND is critical, particularly for a disease with no cure. My PhD was a continuation of my honours research, which meant I could hit the ground running with the lab work.

We identified a large whanau across Aotearoa and Australia living with MND with or without frontotemporal dementia, all harbouring a p.Thr487Ile genetic variant in my gene of interest, UBQLN2. At the time, this variant’s causative link to MND was uncertain, and was complicated by the fact that the presence of ubiquilin 2 protein aggregates in the brain and spinal cord was not exclusive to mutant UBQLN2-MND cases, but is also found in MND cases caused by hexanucleotide expansions in C9orf72, where UBQLN2 is wildtype. Using donated post-mortem brain tissue from the Neurological Foundation Brain Bank at the Centre for Brain Research in Auckland, we found a hippocampal neuropathological signature of MND shared by pathogenic UBQLN2 cases, including the variant of uncertain significance p.Thr487Ile, helping to support its reclassification as a pathogenic genetic cause of MND.

A massive congratulations on being awarded the prestigious Dawn Fellowship from the Neurological Foundation. I can imagine this is career-changing and very exciting. Can you speak about the process of being awarded this fellowship and how this will enable you to continue your research?

Thank you so much. Being awarded this fellowship is such a privilege! This fellowship will allow me to continue my research for another two years in the Motor Neuron Disease Research Lab. These fellowships are instrumental in driving research and kick-starting early career researchers – I am very grateful to the Neurological Foundation and Dawn Estate for this support. The Dawn Fellowship primarily funds projects that investigate dementia in some form, and as mentioned before, UBQLN2-linked MND can also manifest as frontotemporal dementia. This meant that my findings would be relevant, and I qualified, so that was really exciting.

The process of applying for fellowships was and still is very new for me– these processes aren’t taught to you as students. Luckily, I have an incredible and collaborative support network and could reach out to several lab members and colleagues who had been through this process before - their help was invaluable. For this particular fellowship, I submitted a research proposal and had an interview with the Neurological Foundation awards panel. Before this, I had some friends conduct a practice interview with me, which was nerve-wracking but prepared me well. The interview itself flew by and was a great discussion of the proposed work, but also of myself as a researcher. A few months later, I was notified that I was awarded the fellowship, and this was such a relief.

Can you tell us about the project that you are now undertaking while on the Dawn Fellowship?

During my PhD, I conducted a meta-analysis of all previous UBQLN2-linked MND studies, identifying disease characteristics such as age-at-onset, age-at-death, disease duration, co-morbid symptoms and so on. We identified sex-specific differences in these characteristics, with males showing an earlier age at onset of approximately 20 years, and a greater ubiquilin 2 protein aggregate burden in a small sample of cases. As UBQLN2 is found on the X-chromosome, we suspect female protection may derive from a developmental process called X-chromosome inactivation, whereby one X-chromosome in every female cell is randomly inactivated. In heterozygous females, this presents ordinarily as a 50:50 mix of wild-type and mutant allele expression across female tissues.  

Through the generous donation of skin cells (fibroblasts) by individuals carrying the pathogenic p.Thr487Ile UBQLN2 variant, induced pluripotent stem cells (iPSCs) were created with either a wild-type or mutant UBQLN2 allele expressing. Using these iPSCs, I aim to differentiate them into lower motor neurons and generate mosaic cultures to model X-linked disease, assessing cellular and non-cell-autonomous implications of pathogenic UBQLN2 with respect to changes in its protein function and interactions, as well as cellular transcriptomics and proteomics.

I especially want to highlight the generosity and contribution of this kiwi family – it has been invaluable in our understanding of UBQLN2-linked MND, and because it’s so close to home, it has really driven our passion to understand and ultimately treat this devastating disease.

What advice would you give to new PhD students now that you have finished?

This sounds very predictable, but start writing early! Getting your thoughts on paper is important, and developing your ideas over time is crucial. Additionally, don’t be nervous about new and seemingly challenging techniques. Your PhD is the time to learn new things, fail, and try again. It is all about getting new experiences. Most importantly, lean on your network. It takes a village to get through a PhD; no one can do it alone. Find some friends in your department or institute and help each other get through it. The PhD may sound like a long time, but it flies by. Make the most of presenting your work at national and international conferences, and upskilling in any way you can. Enjoy it!

If people want to contact you, how should they do so? Do you have any social media profiles people can follow? 

Please feel free to email me at k.thumbadoo@auckland.ac.nz if you’d like to get in touch. I’m also on LinkedIn (mainly for the games) if you’d like to reach out to me there 😊

Interviewed by Lily Bentall (University of Otago)