From pathways to targets: Untangling the molecular mechanisms of neurodegeneration using ultra-sensitive optical imaging

The prevalence of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease (MND) is rising rapidly in modern ageing societies. There are more than 750,000 people with these devastating disorders living in the UK, and over the next 30-years, the prevalence is estimated to increase to more than 2 million.

If the onset of dementia is delayed by five years, 850 thousand fewer people will be living with these diseases by 2050. However, currently, no treatment exists that can protect neurons in these conditions or slow disease progression. Unless effective treatments, or preventions are found, the burden of these devastating disorders threatens to overwhelm our social and health services.

Most neurodegenerative diseases share a hallmark feature which is the inappropriate deposition of disease-specific protein(s) in the central nervous system. For example, Alzheimer's disease is commonly characterised by the deposition of two different proteins - amyloid-beta and tau - in or around the nerve cells. In contrast, deposition of alpha-synuclein and TDP-43 protein are the hallmark features of Parkinson's disease and motor neuron disease, respectively.

These normally functioning proteins or peptides stick to each other, under certain conditions, within or around nerve cells to form a variety of clumps. These clumps, based on their physical and chemical features, can spread through interconnected regions of the central nervous system in a specific manner causing injury or death to the nerve cells. However, we do not entirely understand how these clumps initially form, how they spread during disease progression and which of them are the most harmful.

As a UKRI Future Leader Fellow at the University of Sheffield Institute for Translational Neuroscience, my goal will be to develop a reliable model and sensitive methods to study the aggregation and propagation of disease-relevant proteins. I will focus on a group of disease called tauopathies, which are characterised by the deposition of a specific protein called tau.

I will use skin cells from tauopathy patients and reprogram them to make different types of nerve cells in a dish. These reprogrammed nerve cells will recapitulate the start and spread of disease in a similar manner as happens in the human brain. Then I will develop ultrasensitive microscopy methods to visualise individual disease-causing tau aggregates in this patient-derived nerve cell model system.

I will determine how disease-relevant tau species initially form, how these species spread through the connected network of the cellular system, which types of tau species are most damaging to the nerve cells and how they damage the nerve cells to contribute to disease progression.

I will compare the role of tau protein in various tau-induced neurodegenerative diseases such as Alzheimer's disease, Pick's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, and determine why these diseases show different clinical symptoms, variable rates of disease progression and different ages of disease onset. I will determine the commonalities and dissimilarities of tau aggregation and propagation pathways in models of these diseases, which will help to discriminate between the patients with distinct tauopathies and might be essential for successful diagnostics, especially at the early stages of the disease, as well as allowing the development of strategies to mitigate tau protein-induced neuronal damage.

Developing reliable methods to detect and monitor individual tau proteins in relevant model systems will accelerate our mechanistic understanding of tau aggregation and spread as it happens in the human brain which, in turn, will provide the critical insights needed to accelerate new therapeutic approaches.