Abnormal build-up of a protein called TDP-43 is a hallmark of many brain diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Around half of people with Alzheimer’s disease (AD) also show TDP-43 build-up, and those who do often experience a more severe disease course.

Normally, cells carefully balance how much TDP-43 they make. In these diseases, that balance is lost, causing the protein to accumulate and form toxic clumps. These clumps can trap newly made TDP-43, creating a toxic cycle that damages neurons and worsens disease. My research shows that tiny chemical tags on RNA—the genetic template for making proteins—act like switches that control how much TDP-43 is produced. By removing these marks, it may be possible to restore this balance and stop the harmful cycle.

In this project, I will identify the exact sites of the RNA tags that control TDP-43 levels in neurons, develop a tool to selectively remove these marks and test whether this restores TDP-43 balance and stops the cycle of clumping that damages neurons. This tool is designed with safety and precision in mind and will only be activated in diseased neurons, minimizing toxic effects on healthy cells.

If successful, this research could pave the way for a new type of RNA-based therapy that slows the progression of ALS, FTD, and AD by tackling a key process that drives disease.