Salvatella Team - Transcription condensates and protein aggregation in SBMA
Summary Description
Spinal and bulbar muscular atrophy (SBMA) is a rare inherited disease that affects motor neurons and muscles, causing progressive weakness. It is caused by an abnormal expansion of a stretch of glutamine residues, called a polyglutamine (polyQ) tract, in the androgen receptor (AR), a protein that helps regulate gene activity in response to male hormones. Recent discoveries have shown that the AR does not work alone, but rather forms small droplets inside cells, known as biomolecular condensates, which gather the necessary molecular machinery for gene regulation. However, these droplets can lose their liquid nature and turn into protein clumps or aggregates, as happens in some neurodegenerative and neuromuscular diseases. We have found that the shape and flexibility of the polyQ tract (its ability to adopt a helical structure) plays a key role in whether AR forms liquid droplets or solid aggregates. Importantly, we found that even small changes in the polyQ structure can protect against protein aggregation. In this project, we aim to better understand how changes in the polyQ tract affect the AR’s behavior in test tubes, in living cells, and in fruit fly models of SBMA. We will also design and test a helical peptide that could prevent the AR from forming aggregates. This could serve as a promising starting point for developing new treatments for SBMA. By uncovering the physical and biological rules behind AR’s change from a functional protein to one that forms aggregates, we hope to provide both a clearer picture of what causes SBMA and new tools to fight it.
