POLYMND: Polyamine dysregulation in Motor Neuron Disease as a targetable driver of astrocyte–neuron dysfunction

Every 45 minutes, someone in Europe dies from amyotrophic lateral sclerosis (ALS), a fatal disease that causes progressive muscle weakness, paralysis, and, eventually, death. With no cure available, there is an urgent need to explore new mechanisms and human-relevant models that could inform treatments. While most research has focused on the nerve cells, called neurons, that die in ALS, growing evidence suggests that other cells in the brain and spinal cord, particularly astrocytes which normally help and protect neurons, may actually contribute to their loss. This project will investigate whether a chemical imbalance in astrocytes plays a hidden but important role in ALS, a fresh but well-grounded concept. Specifically, I will focus on polyamines, small molecules that are vital for healthy brain function, including cell stress responses and communication between cells. In ALS, astrocytes may lose control over polyamine levels, turning a helpful process into a harmful one that damages neurons. The research aims to dissect the cell-type-specific role of polyamine metabolism in ALS pathogenesis and to test whether restoring polyamine balance can rescue disease-related phenotypes. To explore this, I will use stem cell technology to create miniature 3D human brain-like structures (organoids) from the cells of people with ALS. This will allow me to study how astrocytes malfunction in ALS, how polyamine metabolism is disrupted, and whether spermidine, a naturally occurring polyamine found in certain foods, can restore balance and reduce cellular damage. By uncovering and targeting a hidden metabolic weakness in ALS, this research could open the door to new therapies that aim to slow disease progression and preserve the cells and connections that keep people moving, speaking, and living.