Mechanistic Modelling of PSP Tau Progression Using Spatial Transcriptomics

Pathway Grant

Patrick Cullinane, University College London

Progressive supranuclear palsy (PSP) is a rare and currently untreatable brain disease that causes problems with movement, balance, speech, and vision. People with PSP can have very different symptoms and progress at very different speeds, which often delays diagnosis and makes it difficult to select participants for clinical trials. The reasons for these differences are not well understood.

Our previous research shows that PSP spreads through the brain in more than one way. Although similar brain areas are usually affected, they become involved in different sequences and to different extents, giving rise to distinct combinations of symptoms. This project will investigate the molecular changes, meaning differences in how genes are switched on and off in brain cells, that explain why these different forms occur and why some parts of the brain are more vulnerable than others.  We will study brain tissue donated by people with PSP using an advanced technology called spatial transcriptomics. This method allows us to measure gene activity within intact brain tissue and link these molecular changes to the specific regions and cell types in which they occur. We will examine how the activity of brain cells called astrocytes and microglia varies between brain regions and across PSP types.

We will then combine these molecular findings with detailed maps showing where tau, the abnormal protein that builds up inside brain cells and causes damage, accumulates in the brain. This will allow us to understand why PSP affects some brain regions more than others and why the disease progresses differently between people. The results will improve understanding of PSP, help identify molecular markers for earlier and more accurate diagnosis, and highlight new targets for treatment.