Finding Novel Splicing Factors and RNA-binding Proteins that Alter Tau
Alzheimer's disease (AD) is part of a larger group of diseases that cause a protein known as “tau” to accumulate abnormally in the brain. Normally, in the healthy brain, tau fulfills several functions critical for neuron health, and to carry out those assignments, it has the ability to change its length and features through a process known as splicing. However, tau can also undergo detrimental changes that cause it to mistakenly include the wrong features, including to become misshapen and devolve into neurofibrillary tangles that destabilize neurons. This transformation leads to a class of neurodegenerative diseases known as “tauopathies.” There are six different versions of tau protein in the human brain, and it is thought that an imbalance of the different versions result in their abnormal accumulation and subsequent development of a tauopathy. This project aims to discover what genes are responsible for regulating the different versions of tau so that we may better understand how and why an imbalance occurs, and what we could do to fix it.
The main goal of our project is to identify and characterize which genes are responsible for regulating tau splicing, so that we may better understand how imbalances occur, and how we could prevent it.
To achieve this, we will first aim to replicate our preliminary analysis, which correlated the expression of all known splicing-associated genes with the different versions of tau in the brain, in a second, independent gene expression data set. This will give us a panel of candidate genes of interest that may be involved in tau splicing. We will also further analyze these data to more fully characterize tau splicing between different tau haplotypes and regions of the brain. Following this, we aim to validate the effect of our candidate splicing genes on tau splicing in cell models, in order to support our hypothesis that the expression of these genes can indeed alter tau splicing and are not just correlated with it. Finally, we aim to confirm the molecular associations between our candidate genes and tau. This will be achieved by determining whether they localize to the same region of the cell in human brain tissues, and whether they can directly bind to each other.
This project is a unique investigation into tau splicing; an unbiased approach to identifying splicing-associated genes that alter tau has never been conducted before. We anticipate that this will uncover many novel associations and genes that have not been previously considered. The main proportion of our analysis is to be conducted on human brain tissues, which enhances the clinical relevance of our work. Our main strength is the integration of multiple techniques and approaches within this project; we are using computational and 'big data' methods to initially identify our genes of interest, which we will then validate in cell culture, and will finally fully characterize back in human brain tissues.
Following the completion of this project, we will have a much more thorough understanding of the regulation of tau splicing in the brain. This is hugely beneficial to the research field, as we can use this knowledge to make better, more accurate cell models in which we can research the disease 'in a dish.' The wider implication of this project is that it will also provide multiple new targets of interest that may aid in the development of new therapeutics and treatments by allowing us to directly influence the imbalance of tau splicing that is present in many tauopathies.
About the Researcher
I am a postdoctoral fellow with six years’ experience researching neurodegenerative diseases using a range of cellular, molecular and genetic approaches. Following completion of my undergraduate degree in psychology and cognitive neuroscience at the University of Nottingham, UK, I went on to win a Wellcome Trust PhD studentship for the Integrative Neuroscience program at Cardiff University, UK. My PhD research focused on the dysregulation of kinase signaling in Huntington's disease, and how this may alter the subcellular localization of the protein Huntingtin. Following completion of my PhD in 2013, I won a seed fund award from the European Huntington's Disease Network to investigate the role of SMAD transcription factors in the context of Huntington's disease. For the past 2 years, I have been working as a postdoctoral fellow in Dr. Alison Goate's laboratory at the Icahn School of Medicine at Mount Sinai, New York, NY. My research uses computational, genetic and molecular techniques to understand the regulation of tau genetics and splicing in human tissues and in induced pluripotent stem cell (iPSC)-derived cell lines (ie, cells regenerated using tissue samples from living adults). I am interested in the normal regulation of tau expression, and how this associates with and differs among multiple tauopathies.
I followed a winding road from high school to the career and position I am in now. When I applied to university, I had no idea what career I wanted to chase, so I chose to do a degree in the subject I enjoyed most at school, which was psychology. While doing my degree, it took me a while to realize that it wasn't psychology I was actually interested in, but that I was fascinated by the biology of the brain and the minutiae of how neurons functioned. It was only towards the end of my degree that I realized a career in scientific research was even an option, having never known a scientist or been told about it in school, and so I decided that is what I would do!
My grandmother had passed away a few years earlier from complications associated with Alzheimer's, and it was around this time that my other grandmother was also starting to show the signs of dementia. These experiences, together with my new-found enjoyment for research, helped me decided that I wanted to research neurodegeneration, although I was still unsure as to how to go about it. I was lucky enough to win a place on a Wellcome Trust-funded Integrative Neuroscience PhD program, which incorporated multiple different approaches to neuroscience research in the first year, then allowed students to specialize in one particular area in the remaining three years. This is when I discovered molecular biology and biochemistry and finally found what it was I wanted to do! The first couple of years proved challenging, as I had dropped physics and chemistry when I was 16 years old and had never held a pipette in my life. Thankfully, my supervisor was happy to accept me into her lab and train me up into a proper scientist! Ever since then I haven't looked back, and have always pushed myself to learn more techniques and approaches to further my research.
I recently made another leap by moving from the UK to New York, and have extended my research to incorporate genetics and bioinformatics, which seemed like such distant and incomprehensible subjects to me just a few years ago. My training and my experiences have led me to firmly believe that the future of research and of understanding the brain lies in the integration of different techniques and approaches and widespread collaboration among researchers of varying disciplines. That is where the future lies and how we will solve a complex neurodegenerative disease such as Alzheimer’s.
First published on: August 24, 2017
Last modified on: June 30, 2019